This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase (DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.

Nanoparticles have attracted growing interest in recent years. They are small and can easily penetrate into cells. We investigated the genotoxic, cytotoxic, and apoptotic effects of zirconium nanoparticles on dermal fibroblast cells, the comet assay, Xcelligence system, and apoptotic gene expression, respectively. The comet assay analysis showed a non-signifcant increase in the genetic damage index and the percentage of damaged cells in the groups exposed to 10 and 20-nm zirconium oxide nanoparticles. Xcelligence system analysis observed a decrease in the indices of cells exposed to 10 and 20 nm zirconium oxide nanoparticles in the 48th-hour, 72nd-hour, and 96th-hour data. It was observed that caspase 3 and caspase 8 gene expression levels were suppressed in cells exposed to 10 and 20 nm zirconium oxide nanoparticles. Compared to the negative control group, this suppression was significant in the 10 nm groups (p < 0.01) while it was not significant in the 20 nm groups. Although zirconium oxide nanoparticles do not show toxicity and genotoxicity at a given concentration, but the overall mechanism is still not clear regarding the consequences of these nanoparticles use and its efect on living system. However, our apoptotic gene expression studies concluded that the nanoparticle size, particularly 10 nm, had an impact on gene expression.

The investigation of proteins at the single-molecule level is urgent to reveal the relationship between their structure and function. Unlike traditional techniques for attaining the overall average effect of group systems, nanopore sensing mode can provide information on the characteristics of proteins at the single-molecule level. Assisting with the intensity, frequency, and period of current changes, nanopore sequencing technology is rapidly advancing due to its merits, including fast readout, high accuracy, low cost, and portability. In particular, the single-molecule nanopore sequencing mode enables in-depth studies of DNA-protein interactions, protein conformation, DNA sequencing, and microbial assay, including genome sequencing of new species. This review summarizes the sensing mechanisms of nanopore sequencing technology in DNA damage, DNA methylation, RNA sequencing, and protein post-translational modifications and unfolding, covering both biological and solid-state nanopores. Due to these significant advantages, nanopore sequencing provides new insights into complex biological processes and enables more precise real-time monitoring of molecular changes. Its applications extend to clinical diagnostics, environmental monitoring, food safety, and forensic analysis. Moreover, the review outlines the present challenges faced by nanopore sequencing patterns, such as the choice of raw reagents and the design of special construction, offering a deep understanding of nanoporous single-molecule sensing toward protein sequence information and structure prediction.

Fanconi anemia supplementation group I (FANCI), one of the Fanconi family proteins, may be closely related to the malignant progression of glioma cells. Here, we sought to validate the expression of FANCI in glioma cells and its role in regulating the Akt signaling pathway in the malignant progression of glioma cells.

The expression of FANCI in glioma cells was analyzed by bioinformatics and microarray. Lentivirus transfection was used to regulate the expression of FANCI in glioma cells. CCK-8, EdU, Transwell, and flow cytometry were used to observe the effect of FANCI on the malignant progression of glioma cells.

We found that low expression of FANCI inhibited the proliferation, migration and invasion of human glioma cells, and promoted cell apoptosis. However, overexpression of FANCI produced the opposite effect. We also found that low expression of FANCI inhibited the expression of P-Akt and B-cell lymphoma-2 (Bcl-2). Finally, we validated these in vitro results in a xenograft mouse model.

FANCI can inhibit the development of glioma by inhibiting Akt/Bcl-2 signaling pathway.

Enzymatic reactions in cells control the diversity of biomolecular composition, structure, and function, by virtue of their dynamics and heterogeneity. Here, we describe the use of a protein nanopore to monitor, in real time, the action of Exonuclease I (Exo I) on its substrate (homogeneous and heterogeneous short single-stranded DNA, ssDNA) on a single-reactant molecule basis. The nanopore-based single-molecule measurement, combined with a transition kinetic analysis, determines the temporal dynamics and heterogeneous cleavage and release pathways of ssDNA by Exo I. The results demonstrate a stepwise cleavage that is sequence-dependent on short ssDNA molecules (<15 nt), which differs from the kinetic model based on bulk measurements. In addition, we show that damaged DNA irreversibly changes the enzymatic reaction processes by Exo I. Thus, nanopores might prove to be useful for studying multienzyme cascade reactions at the single-molecule level.

Vascular ageing is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular ageing, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular ageing.

We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of ageing, and ECM proteomics in mice from 22 to 72 w. Vascular ageing was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalized all parameters to 72 w. ECM proteomics identified major changes in collagens with ageing, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness.

Vascular ageing is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular ageing, associated with changes in ECM regulatory proteins including LOX and WISP2.

Cells may be intrinsically fated to die to sculpt tissues during development or to maintain homeostasis. Cells can also die in response to various stressors, injury or pathological conditions. Additionally, cells of the metazoan body are often highly specialized with distinct domains that differ both structurally and with respect to their neighbors. Specialized cells can also die, as in normal brain development or pathological states and their different regions may be eliminated via different programs. Clearance of different types of cell debris must be performed quickly and efficiently to prevent autoimmunity and secondary necrosis of neighboring cells. Moreover, all cells, including those programmed to die, may be subject to various stressors. Some largely unexplored questions include whether predestined cell elimination during development could be altered by stress, if adaptive stress responses exist and if polarized cells may need compartment-specific stress-adaptive programs. We leveraged Compartmentalized Cell Elimination (CCE) in the nematode C. elegans to explore these questions. CCE is a developmental cell death program whereby three segments of two embryonic polarized cell types are eliminated differently. We have previously employed this in vivo genetic system to uncover a cell compartment-specific, cell non-autonomous clearance function of the fusogen EFF-1 in phagosome closure during corpse internalization. Here, we introduce an adaptive response that serves to aid developmental phagocytosis as a part of CCE during stress. We employ a combination of forward and reverse genetics, CRISPR/Cas9 gene editing, stress response assays and advanced fluorescence microscopy. Specifically, we report that, under heat stress, the selective autophagy receptor SQST-1/p62 promotes the nuclear translocation of the oxidative stress-related transcription factor SKN-1/Nrf via negative regulation of WDR-23. This in turn allows SKN-1/Nrf to transcribe lyst-1/LYST (lysosomal trafficking associated gene) which subsequently promotes the phagocytic resolution of the developmentally-killed internalized cell even under stress conditions.

The main information in DNA is its four-letter sequence that builds up the genetic information and that is traditionally read using sequencing methodologies. DNA can, however, also carry other important information, such as epigenetic marks and DNA damage. This information has recently been visualized along single DNA molecules using fluorescent labels. Quantifying fluorescent labels along DNA is done by counting the number of "dots" per length of each DNA molecule on DNA stretched on a glass surface. So far, a major challenge has been the lack of standardized data analysis tools. Focusing on DNA damage, we here present a Matlab-based automated software, Stained DNA Dot Detection (SD3), which uses a robust method for finding DNA molecules and estimating the number of dots along each molecule. We have validated SD3 by comparing the outcome to manual analysis using DNA extracted from cells exposed to H2O2 as a model system. Our results show that SD3 achieves high accuracy and reduced analysis time relative to manual counting. SD3 allows the user to define specific parameters regarding the DNA molecule and the location of dots to include during analysis via a user-friendly interface. We foresee that our open-source software can have broad use in the analysis of single DNA molecules and their modifications in research and in diagnostics.

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

Cancer represents a significant disease that profoundly impacts human health and longevity. Projections indicate a 47% increase in the global cancer burden by 2040 compared to 2020, accompanied by a further rise in the associated economic burden. Consequently, there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer. Natural products (NPs) play a crucial role in the identification and development of anticancer therapeutics. This study identified ustusolate E (UE) and its analog 11α-hydroxy-ustusolate E (HUE) from strain Aspergilluscalidoustus TJ403-EL05, and examined their antitumor activities and mechanisms of action. The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS (human gastric cancer cells) and 786-O (human renal clear cell carcinoma cells), induced irreversible DNA damage, blocked the cell cycle at the G2/M phase, and further induced apoptosis in tumor cells. To the best of the authors' knowledge, this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms. The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.

Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair, and its inhibition in cancer cells may cause cell apoptosis. In this study, we investigated the effects of a PARP1 variant, V762A, which is strongly associated with several cancers in humans, on the inhibition of PARP1 by three FDA-approved inhibitors: niraparib, rucaparib, and talazoparib. Specifically, we compared the inhibition of the mutant to that of wild-type (WT) PARP1. Additionally, we investigated how the mutation influences the binding of these inhibitors to PARP1. Our work suggests that while mutant PARP1 exhibits only minor differences in residual fluctuations, backbone deviations, and residue motion correlations compared to the WT under niraparib and rucaparib inhibitions, it shows significant and distinct differences in these features when inhibited by talazoparib. Among the three inhibitions, talazoparib inhibition uniquely lowers the average residue fluctuations in the mutant than the WT including lower fluctuations of mutant's N- and C-terminal residues in the catalytic domain, conserved H-Y-E traid residues, and donor loop (D-loop) residues which are important for catalysis more effectively than other inhibitions. However, talazoparib also significantly enhances destabilizing interactions between the mutation site in the HD domain in the mutant than WT. Further, among the three inhibitions, talazoparib inhibition uniquely and significantly disrupts the functional fluctuations of terminal regions in the mutant, which are otherwise present in the WT. The mutation and inhibition do not significantly affect PARP1's essential dynamics. Lastly, these inhibitors bind to the V762A mutant more effectively than to the WT, with similar binding free energies between them.

Although significant advances in understanding the molecular drivers of acquired and inherited radiosensitivity have occurred in recent decades, a single analytical method which can detect and classify radiosensitivity remains elusive. Raman microspectroscopy has demonstrated capabilities in the objective classification of various diseases, and more recently in the detection and modelling of radiobiological effect. In this study, Raman spectroscopy is presented as a potential tool for the detection of radiosensitivity subpopulations represented by four lymphoblastoid cell lines derived from individuals with ataxia telangiectasia (2 lines), non-Hodgkins lymphoma, and Turner's syndrome. These are classified with respect to a population with mixed radiosensitivity, represented by lymphocytes drawn from both healthy controls, and prostate cancer patients. Raman spectroscopic measurements were made ex-vivo after exposure to X-ray doses of 0 Gy, 50 mGy and 500 mGy, in parallel to radiation-induced G2 chromosomal radiosensitivity scores, for all samples. Support vector machine models developed on the basis of the spectral data were capable of discrimination of radiosensitive populations before and after irradiation, with superior discrimination when spectra were subjected to a non-linear dimensionality reduction (UMAP) as opposed to a linear (PCA) approach. Models developed on spectral data acquired on samples irradiated in-vitro with a dose of 0Gy were found to provide the highest level of performance in discriminating between classes, with performances of F1 = 0.92 ± 0.06 achieved on a held-out test set. Overall, this study suggests that Raman spectroscopy may have potential as a tool for the detection of intrinsic radiosensitivity using liquid biopsies.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85% of all cases, with a poor 5-year survival rate of less than 20%. The majority of NSCLC patients are diagnosed at an advanced stage, contributing to the low survival rate. Platinum-based chemotherapy, including cisplatin and carboplatin, remains the cornerstone of treatment for advanced NSCLC. However, DNA repair mechanisms often hinder treatment efficacy, notably Base Excision Repair (BER), mediated by the X-ray Repair Cross Complementing 1 (XRCC1) protein. This review aims to investigate the role of XRCC1 polymorphisms in platinum resistance, focusing on their impact on DNA repair efficiency. XRCC1's involvement in the BER pathway is critical for repairing DNA damage caused by platinum agents, and polymorphisms in XRCC1 have been linked to altered repair capacity, influencing clinical outcomes and resistance to platinum-based chemotherapy in NSCLC patients.

The differential use of synonymous codons of an amino acid is an imperative evolutionary phenomenon, termed codon usage bias, that functions across various levels of organisms. It is accustomed to providing an understanding of a gene's differential architecture driven by functional regulation of gene expression. Numerous synonymous mutations are linked to various diseases, demonstrating that silent mutations can be deleterious. We employed bioinformatics methods to examine codon usage trends in 263 coding sequences of 44 blood group systems. The blood group systems were categorized into two groups based on association with a sort of neurodegenerative disorder. We performed a CUB study to investigate how multiple components, such as selection, mutation and biased nucleotide composition are accountable for the evolution of the transcripts of the blood group antigens. The compositional analysis implicated blood group genes were GC-rich. RSCU analysis showed G/C-ending codon choice among synonymous codons. Also, a distinct codon choice was found in both blood groups for serine and proline. Moreover, the leucine-coding CTG codon was found the most overrepresented in all the genes, indicating selectional pressure substantially impacts overall codon usage. This was also supported by biplot analysis. Additionally, CpC and GpG overrepresentation is in concordance with the results concerning neurodegenerative disorders where CpC has been attributed to non-CpG methylation and linked to several neurodegenerative ailments. Both the Z-test analysis and rare codon choice showed a substantial difference in codon usage by the genes of both groups.

Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key player of the NER pathway in eukaryotes. This 10-subunit multiprotein complex notably verifies the presence of a lesion and opens the DNA around the damage via its XPB and XPD subunits, two proteins identified in patients suffering from Xeroderma Pigmentosum syndrome. Isolated as a class II gene transcription factor in the late 1980s, TFIIH is a prototypic molecular machine that plays an essential role in both DNA repair and transcription initiation and harbors a DNA helicase, a DNA translocase, and kinase activity. More recently, TFIIH subunits have been identified as participating in other cellular processes, including chromosome segregation during mitosis, maintenance of mitochondrial DNA integrity, and telomere replication.

The combination of genetic and environmental factors may contribute to the carcinogenesis of HNC. Despite the reported associations between xeroderma pigmentosum group D (XPD) polymorphisms and HNC, the results have been inconsistent, with different studies reporting varying results. Therefore, our aim is to assess the association of three XPD polymorphisms (rs13181, rs1799793, and rs238406) in a comprehensive meta-analysis.

An exhaustive literature review was performed across several databases, including PubMed, Web of Science, Scopus, and Cochrane Library, up to November 18, 2023, without any restrictions. The effect sizes were presented as the odds ratio (OR) with a 95% confidence interval (CI).

Thirty-nine articles including 56 studies were entered into the meta-analysis. Evaluating rs13181, rs1799793, and rs238406 polymorphisms in five genetic models, just significant associations were found for rs1799793 polymorphism in heterozygous and dominant models. The findings reported that the ethnicity and the cancer subtype for rs13181, the ethnicity, the sample size, and the control source for rs1799793, and the ethnicity and the control source for rs238406 polymorphisms were effective factors in the pooled results. Trial sequential analysis suggested that the studies included an insufficient number of individuals. Sensitivity analysis reported stability of pooled results. The XPD protein variants were predicted to be benign.

The study reveals a significant association between the rs1799793 polymorphism and HNC, but not rs13181 and rs238406 polymorphisms. Future studies should also aim to minimize the impact of confounding factors and heterogeneity to ensure more accurate results.

Since an unusual expression of uracil-DNA glycosylase (UDG) is often associated with the pathogenesis of numerous disorders, the detection of UDG activity is regarded as a promising application in disease diagnosis. Here, we develop a DNA polymerase-mediated CRISPR/Cas12a trans cleavage strategy, which can achieve dual-mode determination of UDG activity. By introducing a hairpin DNA probe containing a single uracil base, the probe undergoes specific cleavage and elongation under the existence of UDG only, thus activating the trans cleavage of ssDNA regardless of its length and sequence. To accommodate different detection modes, the ssDNA was further modified by fluorophore-quencher pairs or designed for connecting magnetic microparticles (MMPs) and polystyrene microparticles (PMPs). Finally, the UDG activity is quantified by fluorescence signal and microparticle accumulation length on a microfluidic chip visible to the naked eye. This strategy provides a detectable minimum UDG concentration of 0.00047 U/mL for fluorescent mode and 0.0048 U/mL for microfluidic mode. Furthermore, we performed the UDG inhibition test and detected UDG activity in cell lysates, suggesting its potential for inhibitor screening and detection of UDG in biological samples.

Bacteria encode various DNA repair pathways to maintain genome integrity. However, the high degree of homology between DNA repair proteins or their domains hampers accurate identification. Here, we describe a stringent search strategy to identify DNA repair proteins and provide a systematic analysis of taxonomic distribution and co-occurrence of DNA repair proteins involved in RecA-dependent homologous recombination. Our results reveal the widespread presence of RecA, SSB, and RecOR proteins and phyla-specific distribution for the DNA repair complexes RecBCD, AddAB, and AdnAB. Furthermore, we report co-occurrences of DNA repair proteins with immune systems, including specific CRISPR-Cas subtypes, prokaryotic Argonautes (pAgos), dGTPases, GAPS2, and Wadjet. Our results imply that while certain DNA repair proteins and immune systems might function in conjunction, no immune system strictly relies on a specific DNA repair protein. As such, these findings offer an updated perspective on the distribution of DNA repair systems and their connection to immune systems in bacteria.

The highly active natural product yatakemycin (YTM) from Streptomyces sp. TP-A0356 is a potent DNA damaging agent with antimicrobial and antitumor properties. The YTM biosynthesis gene cluster (ytk) contains several toxin self-resistance genes. Of these, ytkR2 encodes a DNA glycosylase that is important for YTM production and host survival by excising lethal YTM-adenine lesions from the genome, presumably initiating a base excision repair (BER) pathway. However, the genes involved in repair of the resulting apurinic/apyrimidinic (AP) site as the second BER step have not been identified. Here, we show that ytkR4 and ytkR5 are essential for YTM production and encode deoxyribonucleases related to other known DNA repair nucleases. Purified YtkR4 and YtkR5 exhibit AP endonuclease activity specific for YtkR2-generated AP sites, providing a basis for BER of the toxic AP intermediate produced from YTM-adenine excision and consistent with co-evolution of ytkR2, ytkR4, and ytkR5. YtkR4 and YtkR5 also exhibit 3'-5' exonuclease activity with differing substrate specificities. The YtkR5 exonuclease is capable of digesting through a YTM-DNA lesion and may represent an alternative repair mechanism to BER. We also show that ytkR4 and ytkR5 homologs are often clustered together in putative gene clusters related to natural product production, consistent with non-redundant roles in repair of other DNA adducts derived from genotoxic natural products.

The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development1-3. Although numerous cell-intrinsic mechanisms have been revealed4-7, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua-knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.

Cancer cell dormancy is a critical phase in cancer development, wherein cancer cells exist in a latent state marked by temporary but reversible growth arrest. This dormancy phase contributes to anticancer drug resistance, cancer recurrence, and metastasis. Treatment strategies aimed at cancer dormancy can be categorized into two contradictory approaches: inducing cancer cells into a dormant state or eliminating dormant cells. While the former seeks to establish permanent dormancy, the latter aims at eradicating this small population of dormant cells. In this review, we explore the current advancements in therapeutic methods targeting cancer cell dormancy and discuss future strategies. The concept of cancer cell dormancy has emerged as a promising avenue for novel cancer treatments, holding the potential for breakthroughs in the future.

Venous thromboembolism (VTE) is the third most common cardiovascular disease and is a major cause of mobility and mortality worldwide. VTE is a complex multifactorial disease and genetic mechanisms underlying its pathogenesis is yet to be completely elucidated. The aim of the present study was to identify hub genes and pathways involved in development and progression of blood clot during VTE using gene expression data from public repositories.

Differential gene expression (DEG) data from two datasets, GSE48000 and GSE19151 were analysed using GEO2R tool. Gene expression data of VTE patients were compared to that of healthy controls using various bioinformatics tools.

When the differentially expressed genes of the two datasets were compared, it was found that 19 genes were up-regulated while 134 genes were down-regulated. Gene ontology (GO) and pathway analysis revealed that pathways such as complement and coagulation cascade and B-cell receptor signalling along with DNA methylation, DNA alkylation and inflammatory genes were significantly up-regulated in VTE patients. On the other hand, differentially down-regulated genes included mitochondrial translation elongation, termination and biosysthesis along with heme biosynthesis, erythrocyte differentiation and homeostasis. The top 5 up-regulated hub genes obtained by protein-protein interaction (PPI) network analysis included MYC, FOS, SGK1, CR2 and CXCR4, whereas the top 5 down-regulated hub genes included MRPL13, MRPL3, MRPL11, RPS29 and RPL9. The up-regulated hub genes are functionally involved in maintain vascular integrity and complementation cascade while the down-regulated hub genes were mostly mitochondrial ribosomal proteins.

Present study highlights significantly enriched pathways and genes associated with VTE development and prognosis. The data hereby obtained could be used for designing newer diagnostic and therapeutic tools for VTE management.

Cases with central nervous system tumors represent a small amount of all tumors, and the diagnosis of high-grade gliomas (HGGs) is mostly difficult as they frequently show intratumoral morphological heterogeneity. Genetic factors, such as single nucleotide polymorphisms (SNPs), have an important role in modifying glioma susceptibility. We conducted a comprehensive meta-analysis to investigate the ERCC1 (rs3212986), ERCC2 (rs13181), XRCC1 (rs25487), and XRCC3 (rs861539) genes to see if they are any risk factors for glioma susceptibility. We identified 30 eligible studies investigating the PubMed records (up to January 2024) via a mishmash of the subsequent terms: brain tumors, glioma, glioblastoma, gene associations, SNPs, XRCC1, XRCC3, ERCC1, and ERCC2. The total number of patients was 23678 (9731 in cases (poor outcome) and 13947 in controls (good outcome)). This comprehensive meta-analysis declared a significant association between ERCC2 rs13181, XRCC1 rs25487, and the risk of glioma.

In mammalian cells, DNA ligase 1 (LIG1) functions as the primary DNA ligase in both genomic replication and single-strand break repair. Several reported mutations in human LIG1, including R305Q, R641L, and R771W, cause LIG1 syndrome, a primary immunodeficiency. While the R641L and R771W mutations, respectively located in the nucleotidyl transferase and oligonucleotide binding domains, have been biochemically characterized and shown to reduce catalytic efficiency, the recently reported R305Q mutation within the DNA binding domain (DBD) remains mechanistically unexplored. The R641L and R771W mutations are known to decrease the catalytic activity of LIG1 by affecting both interdomain interactions and DNA binding during catalysis, without significantly impacting overall DNA affinity. To elucidate the molecular basis of the LIG1 syndrome-causing R305Q mutation, we purified this single-residue mutant protein and investigated its secondary structure, protein stability, DNA binding affinity, and catalytic efficiency. Our findings reveal that the R305Q mutation significantly impairs the function of LIG1 by disrupting the DBD-DNA interactions, leading to a 7-21-fold lower DNA binding affinity and a 33-300-fold reduced catalytic efficiency of LIG1. Additionally, the R305Q mutation slightly decreases LIG1's protein stability by 2 to 3.6 °C, on par with the effect observed previously with either the R641L or R771W mutant. Collectively, our results uncover a new mechanism whereby the R305Q mutation impairs LIG1-catalyzed nicked DNA ligation, resulting in LIG1 syndrome, and highlight the crucial roles of the DBD-DNA interactions in tight DNA binding and efficient LIG1 catalysis.

The genome duplication program is affected by multiple factors in vivo, including developmental cues, genotoxic stress, and aging. Here, we monitored DNA replication initiation dynamics in regenerating livers of young and old mice after partial hepatectomy to investigate the impact of aging. In young mice, the origin firing sites were well defined; the majority were located 10-50 kb upstream or downstream of expressed genes, and their position on the genome was conserved in human cells. Old mice displayed the same replication initiation sites, but origin firing was inefficient and accompanied by a replication stress response. Inhibitors of the ATR checkpoint kinase fully restored origin firing efficiency in the old mice but at the expense of an inflammatory response and without significantly enhancing the fraction of hepatocytes entering the cell cycle. These findings unveil aging-dependent replication stress and a crucial role of ATR in mitigating the stress-associated inflammation, a hallmark of aging.

DNA damage is typically caused during cell growth by DNA replication stress or exposure to endogenous or external toxins. The accumulation of damaged DNA causes genomic instability, which is the root cause of many serious disorders. Multiple cellular organisms utilize sophisticated signaling pathways against DNA damage, collectively known as DNA damage response (DDR) networks. Innate immune responses are activated following cellular abnormalities, including DNA damage. Interestingly, recent studies have indicated that there is an intimate relationship between the DDR network and innate immune responses. Diverse kinds of cytosolic DNA sensors, such as cGAS and STING, recognize damaged DNA and induce signals related to innate immune responses, which link defective DDR to innate immunity. Moreover, DDR components operate in immune signaling pathways to induce IFNs and/or a cascade of inflammatory cytokines via direct interactions with innate immune modulators. Consistently, defective DDR factors exacerbate the innate immune imbalance, resulting in severe diseases, including autoimmune disorders and tumorigenesis. Here, the latest progress in understanding crosstalk between the DDR network and innate immune responses is reviewed. Notably, the dual function of innate immune modulators in the DDR network may provide novel insights into understanding and developing targeted immunotherapies for DNA damage-related diseases, even carcinomas.

DNA damage induced by chemotherapy has duality. It affects the efficacy of chemotherapy and constrains its application. An increasing number of studies have shown that traditional Chinese medicine (TCM) is highly effective in reducing side-effects induced by chemotherapy due to its natural, non-toxic and many sourced from food. Recent advancements have demonstrated survival rates are improved attributable to effective chemotherapy. DNA damage is the principal mechanism underlying chemotherapy. However, not all instances of DNA damage are beneficial. Chemotherapy induces DNA damage in normal cells, leading to side effects. It affects the efficacy of chemotherapy and constrains its application.

This review aims to summarize the dual nature of DNA damage induced by chemotherapy and explore how TCM can mitigate chemotherapy-induced side effects.

The review summarized the latest research progress in DNA damage caused by chemotherapy and the effect of alleviating side effects by TCM. It focused on advantages and disadvantages of chemotherapy, the mechanism of drugs and providing insights for rational and effective clinical treatment and serving as a basis for experiment. In this review, we described the mechanisms of DNA damage, associated chemotherapeutics, and their toxicity. Furthermore, we explored Chinese herb that can alleviate chemotherapy-induced side-effects.

We highlight key mechanisms of DNA damage caused by chemotherapeutics and discuss specific TCM herbs that have shown potential in reducing these side effects. It can provide reference for clinical and basic research.

Accurate and reliable detection of uracil-DNA glycosylase (UDG) activity is crucial for clinical diagnosis and prognosis assessment. However, current techniques for accurately monitoring UDG activity still face significant challenges due to the single input or output signal modes. Here, we develop a sequentially activated-dumbbell DNA nanodevice (SEAD) that enables precise and reliable evaluation of UDG activity through primer exchange reactions (PER)-based orthogonal signal output. The SEAD incorporates a double-hairpin structure with a stem containing two deoxyuridine (dU) sites for target recognition and two preblocked primer binding regions for target amplification and signal output. Upon UDG recognition of dU, the SEAD can be cleaved by apurinic/apyrimidinic endonuclease 1 (APE1), generating two different hairpins with exposed primer binding regions. These hairpins serve as templates to initiate the parallel PER, enabling the extending of two different amplification products: a long single-stranded DNA (ssDNA) with repetitive sequences and a short ferrocene-labeled ssDNA with complementary sequences. These products further self-assemble into DNA nano-strings in an orthogonal manner that act as an electrochemiluminescence signal switch, enabling precise detection of low-abundance UDG. This work develops a sequential input and orthogonal output strategy for accurately monitoring UDG activity, highlighting the significant potential in cancer diagnosis and treatment.

Gastrointestinal (GI) cancers, including gastric, liver, esophageal, pancreatic, and colorectal cancers, represent significant global health burdens. Emerging evidence suggests that dietary patterns, particularly their inflammatory and oxidative properties, may influence cancer risk. The Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS) assess the inflammatory and oxidative effects of diets, respectively. This study aims to explore the association between DII, DOBS, and the combined risk of GI cancers, and investigates the potential mediating roles of serum albumin and red cell distribution width (RDW).

Data from 26,320 participants in the NHANES 2005-2018 cycles were analyzed. DII was calculated based on 28 dietary components, and DOBS included 17 nutrients (3 pro-oxidants and 14 antioxidants). Logistic regression models assessed the associations between DII, DOBS, and GI cancers. Restricted cubic spline (RCS) models examined dose-response relationships. Mediation analysis evaluated the roles of serum albumin and RDW. Subgroup analyses explored interactions with demographic and health-related factors.

Higher DII was associated with increased GI cancer risk (OR: 1.26, 95% CI: 1.07-1.49 per unit increase), while higher DOBS was associated with reduced risk (OR: 0.90, 95% CI: 0.76-0.99 per unit increase). RCS analysis indicated a significant nonlinear relationship between DII and GI cancer risk. Serum albumin and RDW partially mediated the associations between DII, DOBS, and GI cancers. Subgroup analyses showed stronger associations for DII among certain demographics, and significant interactions were found between DII and BMI. For DOBS, significant interactions were observed with age and BMI.

This study reveals significant associations between dietary inflammatory and oxidative balance scores and GI cancer risk. Higher DII is linked to increased risk, while higher DOBS is protective. The mediating roles of serum albumin and RDW provide insights into underlying mechanisms. These findings underscore the potential of dietary modifications in GI cancer prevention and management, emphasizing the importance of anti-inflammatory and antioxidant-rich diets.

Homologous recombination deficiency (HRD) is recognized as a pan-cancer predictive biomarker that potentially indicates who could benefit from treatment with PARP inhibitors (PARPi). Despite its clinical significance, HRD testing is highly complex. Here, we investigated in a proof-of-concept study whether Deep Learning (DL) can predict HRD status solely based on routine hematoxylin & eosin (H&E) histology images across nine different cancer types.

We developed a deep learning pipeline with attention-weighted multiple instance learning (attMIL) to predict HRD status from histology images. As part of our approach, we calculated a genomic scar HRD score by combining loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) from whole genome sequencing (WGS) data of n = 5209 patients across two independent cohorts. The model's effectiveness was evaluated using the area under the receiver operating characteristic curve (AUROC), focusing on its accuracy in predicting genomic HRD against a clinically recognized cutoff value.

Our study demonstrated the predictability of genomic HRD status in endometrial, pancreatic, and lung cancers reaching cross-validated AUROCs of 0.79, 0.58, and 0.66, respectively. These predictions generalized well to an external cohort, with AUROCs of 0.93, 0.81, and 0.73. Moreover, a breast cancer-trained image-based HRD classifier yielded an AUROC of 0.78 in the internal validation cohort and was able to predict HRD in endometrial, prostate, and pancreatic cancer with AUROCs of 0.87, 0.84, and 0.67, indicating that a shared HRD-like phenotype occurs across these tumor entities.

This study establishes that HRD can be directly predicted from H&E slides using attMIL, demonstrating its applicability across nine different tumor types.

The superfamily 2 helicase XPD is a central component of the general transcription factor II H (TFIIH), which is essential for transcription and nucleotide excision DNA repair (NER). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where XPD acts only as a scaffold for other factors. Using cryo-EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of double-stranded DNA (dsDNA) and its stalling upon approaching a DNA interstrand cross-link, a highly toxic form of DNA damage. The structure shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identified distinct functional regions important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. In summary, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

DNA damage severely impedes gene transcription by RNA polymerase II (Pol II), causing cellular dysfunction. Transcription-Coupled Nucleotide Excision Repair (TC-NER) specifically removes such transcription-blocking damage. TC-NER initiation relies on the CSB, CSA and UVSSA proteins; loss of any results in complete TC-NER deficiency. Strikingly, UVSSA deficiency results in UV-Sensitive Syndrome (UVSS), with mild cutaneous symptoms, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by neurodegeneration and premature aging. Thus far the underlying mechanism for these contrasting phenotypes remains unclear. Live-cell imaging approaches reveal that in TC-NER proficient cells, lesion-stalled Pol II is swiftly resolved, while in CSA and CSB knockout (KO) cells, elongating Pol II remains damage-bound, likely obstructing other DNA transacting processes and shielding the damage from alternative repair pathways. In contrast, in UVSSA KO cells, Pol II is cleared from the damage via VCP-mediated proteasomal degradation which is fully dependent on the CRL4CSA ubiquitin ligase activity. This Pol II degradation might provide access for alternative repair mechanisms, such as GG-NER, to remove the damage. Collectively, our data indicate that the inability to clear lesion-stalled Pol II from the chromatin, rather than TC-NER deficiency, causes the severe phenotypes observed in CS.

Trypanosoma cruzi is the etiological agent of Chagas disease and a peculiar eukaryote with unique biological characteristics. DNA damage can block RNA polymerase, activating transcription-coupled nucleotide excision repair (TC-NER), a DNA repair pathway specialized in lesions that compromise transcription. If transcriptional stress is unresolved, arrested RNA polymerase can activate programmed cell death. Nonetheless, how this parasite modulates these processes is unknown. Here, we demonstrate that T. cruzi cell death after UV irradiation, a genotoxic agent that generates lesions resolved by TC-NER, depends on active transcription and is signaled mainly by an apoptotic-like pathway. Pre-treated parasites with α-amanitin, a selective RNA polymerase II inhibitor, become resistant to such cell death. Similarly, the gamma pre-irradiated cells are more resistant to UV when the transcription processes are absent. The Cockayne Syndrome B protein (CSB) recognizes blocked RNA polymerase and can initiate TC-NER. Curiously, CSB overexpression increases parasites' cell death shortly after UV exposure. On the other hand, at the same time after irradiation, the single-knockout CSB cells show resistance to the same treatment. UV-induced fast death is signalized by the exposition of phosphatidylserine to the outer layer of the membrane, indicating a cell death mainly by an apoptotic-like pathway. Furthermore, such death is suppressed in WT parasites pre-treated with inhibitors of ataxia telangiectasia and Rad3-related (ATR), a key DDR kinase. Signaling for UV radiation death may be related to R-loops since the overexpression of genes associated with the resolution of these structures suppress it. Together, results suggest that transcription blockage triggered by UV radiation activates an ATR-dependent apoptosis-like mechanism in T. cruzi, with the participation of CSB protein in this process.

The DNA damage repair (DDR) pathway is a complex signaling cascade that can sense DNA damage and trigger cellular responses to DNA damage to maintain genome stability and integrity. A typical hallmark of cancer is genomic instability or nonintegrity, which is closely related to the accumulation of DNA damage within cancer cells. The treatment principles of radiotherapy and chemotherapy for cancer are based on their cytotoxic effects on DNA damage, which are accompanied by severe and unnecessary side effects on normal tissues, including dysregulation of the DDR and induced therapeutic tolerance. As a driving factor for oncogenes or tumor suppressor genes, noncoding RNA (ncRNA) have been shown to play an important role in cancer cell resistance to radiotherapy and chemotherapy. Recently, it has been found that ncRNA can regulate tumor treatment tolerance by altering the DDR induced by radiotherapy or chemotherapy in cancer cells, indicating that ncRNA are potential regulatory factors targeting the DDR to reverse tumor treatment tolerance. This review provides an overview of the basic information and functions of the DDR and ncRNAs in the tolerance or sensitivity of tumors to chemotherapy and radiation therapy. We focused on the impact of ncRNA (mainly microRNA [miRNA], long noncoding RNA [lncRNA], and circular RNA [circRNA]) on cancer treatment by regulating the DDR and the underlying molecular mechanisms of their effects. These findings provide a theoretical basis and new insights for tumor-targeted therapy and the development of novel drugs targeting the DDR or ncRNAs.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies.

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.

Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 (BRCA1 and BRCA2) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and BRCA genes mutations. In recent years, the benefit of combination therapy consisted of a PARP inhibitor (PARPi) plus an androgen receptor signalling inhibitor (ARSi), was evaluated as first-line treatment of mCRPC, regardless of the mutational state of genes, participating in the homologous recombination repair (HRR). This review explores the role of PARPi in PCa and analyses the data of latest clinical trials exploring the PARPi-ARSi combinations, and how these results could change our clinical practice.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.

DNA glycosylases are a group of enzymes that play a crucial role in the DNA repair process by recognizing and removing damaged or incorrect bases from DNA molecules, which maintains the integrity of the genetic information. The abnormal expression of uracil-DNA glycosylase (UDG), one of significant DNA glycosylases in the base-excision repair pathway, is linked to numerous diseases. Here, we proposed a simple UDG activity detection method based on toehold region triggered CRISPR/Cas12a trans-cleavage. The toehold region on hairpin DNA probe (HP) produced by UDG could induce the trans-cleavage of ssDNA with fluorophore and quencher, generating an obvious fluorescence signal. This protospacer adjacent motif (PAM)-free approach achieves remarkable sensitivity and specificity in detecting UDG, with a detection limit as low as 0.000368 U mL-1. Moreover, this method is able to screen inhibitors and measure UDG in complex biological samples. These advantages render it highly promising for applications in clinical diagnosis and drug discovery.

The detrimental effects of ultraviolet radiation (UVR) on human skin are well-documented, encompassing DNA damage, oxidative stress, and an increased risk of carcinogenesis. Conventional photoprotective measures predominantly rely on filters, which scatter or absorb UV radiation, yet fail to address the cellular damage incurred post-exposure. To fill this gap, antioxidant molecules and DNA-repair enzymes have been extensively researched, offering a paradigm shift towards active photoprotection capable of both preventing and reversing UV-induced damage. In the current review, we focused on "active photoprotection", assessing the state-of-the-art, latest advancements and scientific data from clinical trials and in vivo models concerning the use of DNA-repair enzymes and naturally occurring antioxidant molecules.