The use of platinum-based drugs in cancer treatment is one of the most common methods in chemotherapy. Especially, cisplatin induces cell death by interrupting DNA synthesis by binding to the DNA bases, thereby leading to the apoptosis via multiple pathways. However, the major hurdle in chemotherapy is drug resistance. To overcome drug resistance, the ubiquitin-proteasome system (UPS) has emerged as a potential therapeutic target. The UPS is a pivotal signaling pathway that regulates the majority of cellular proteins by attaching ubiquitin to substrates, leading to proteasomal degradation. Conversely, deubiquitinating enzymes (DUBs) remove tagged ubiquitin from the substrate and inhibit degradation, thereby maintaining proteostasis. Recently, studies have been conducted to identify the substrates of DUBs and investigated the cellular mechanisms, and now the development of therapeutics using DUB inhibitors is in clinical trials. However, the mechanism of the DUB response to cisplatin remains still unclear. In this review, we summarize the research reported on the function of DUBs responding to cisplatin.

Bacteria continually evolve. Previous studies have evaluated bacterial evolution in retrospect, but this approach is based on only speculation. Cohort studies are reliable but require a long duration. Additionally, identifying which genetic mutations that have emerged during bacterial evolution possess functions of interest to researchers is an exceptionally challenging task. Here, we establish a Rapid and Integrated Bacterial Evolution Analysis (RIBEA) based on serial passaging experiments using hypermutable strains, whole-genome and transposon-directed sequencing, and in vivo evaluations to monitor bacterial evolution in a cohort for one month. RIBEA reveals bacterial factors contributing to serum and antimicrobial resistance by identifying gene mutations that occurred during evolution in the major respiratory pathogen Klebsiella pneumoniae. RIBEA also enables the evaluation of the risk for the progression and the development of invasive ability from the lung to blood and antimicrobial resistance. Our results demonstrate that RIBEA enables the observation of bacterial evolution and the prediction and identification of clinically relevant high-risk bacterial strains, clarifying the associated pathogenicity and the development of antimicrobial resistance at genetic mutation level.

Huntington's disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis in vivo.

Mismatch repair (MMR) is a highly conserved DNA repair pathway that recognizes mispairs that occur spontaneously during DNA replication and coordinates their repair. In Saccharomyces cerevisiae, Msh2-Msh3 and Msh2-Msh6 initiate MMR by recognizing and binding insertion or deletion (in/del) loops up to ∼17 nucleotides (nt.) and base-base mispairs, respectively; the 2 complexes have overlapping specificity for small (1-2 nt.) in/dels. The DNA-binding specificity for the 2 complexes resides in their respective mispair binding domains (MBDs) and has distinct DNA-binding modes. Msh2-Msh3 also plays a role in promoting CAG/CTG trinucleotide repeat (TNR) expansions, which underlie many neurodegenerative diseases such as Huntington's disease and myotonic dystrophy type 1. Models for Msh2-Msh3's role in promoting TNR tract expansion have invoked its specific DNA-binding activity and predict that the TNR structure alters its DNA binding and downstream activities to block repair. Using a chimeric Msh complex that replaces the MBD of Msh6 with the Msh3 MBD, we demonstrate that Msh2-Msh3 DNA-binding activity is not sufficient to promote TNR expansions. We propose a model for Msh2-Msh3-mediated TNR expansions that requires a fully functional Msh2-Msh3 including DNA binding, coordinated ATP binding, and hydrolysis activities and interactions with Mlh complexes that are analogous to those required for MMR.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of abnormal clonal plasma cells in the bone marrow. The heterogeneity in Chinese MM populations remains underexplored.

We conducted whole-exome sequencing (WES) on 241 tumor samples, complemented by RNA sequencing (RNA-seq) on 131 samples from 212 Chinese MM patients.

We identified a novel mutational signature and analyzed molecular differences between newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. NFKBIA mutations were notably more frequent in NDMM patients compared to the MMRF-COMMPASS cohort (4/50 vs 22/937, p = 0.048), with additional recurrent mutations in several genes like TTN, IGLL5 and SYNE1. In RRMM patients, UBR5 mutations were more prevalent (4/24 vs 0/50, p = 0.01), alongside frequent mutations in OBSCN, CACNA1H, and HSPG2. Clonal evolution was assessed through multiple time points and locations, identifying genes potentially linked to circulating plasma cell formation. Cox regression analysis revealed that age and mutations in OBSCN and RB1 were significant predictors of progression-free survival (PFS) in NDMM patients. Additionally, albumin, β2-microglobulin, and RB1 mutations were correlated with overall survival (OS).

In summary, we characterized the genomic landscape of MM in diverse Chinese populations, confirmed clonal evolution, and identified prognostic genes.

The emergence of immunotherapy has revolutionized the paradigm of cancer treatment with immune checkpoint blockades (ICB) in solid cancers, including colorectal cancer (CRC). However, only a small subset of CRC patients harboring deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) benefits from ICB therapy. A very limited response to ICB therapy has been achieved in MMR-proficient CRC, representing a significant challenge limiting the clinical application of immunotherapy. MMR is the critical DNA repair pathway that maintains genomic integrity by correcting DNA mismatches, which is mediated by the MutSα or MutSβ complex consisting of MSH2 with MSH6 and MSH3, respectively. Given that MMR status directs effective immune response, we sought to determine whether targeting MMR capacity boosts ICB efficacy.

Azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC and xenograft model were used to evaluate the function of PRMT6 and response to PRMT6 inhibitor EPZ020411 and combination therapy of PD1 and EPZ020411. Biochemical assays were performed to elucidate the underlying mechanism of PRMT6-mediated MSH2 methylation and immune evasion.

We have identified PRMT6 as a crucial regulator of MMR capacity via MSH2 dimethylation at R171 and R219. Such a modification abrogates its MMR capacity and prevents the recruitment of MSH3 and MSH6. PRMT6 loss or inhibition triggers cytosolic DNA accumulation and cGAS-STING signaling activation, leading to enhanced immune response in PRMT6-deficient colon tumors or xenografts. Pharmacological inhibition of PRMT6 using EPZ020411 promotes mutagenesis and destabilizes MutSα or MutSβ assembly, and prolonged EPZ020411 exposure maintains an MSI-like phenotype in microsatellite stability (MSS) cells. EPZ020411 treatment sensitizes ICB efficacy of MSS cells, but not MSI cells in vivo. Similar effects have been observed in MSS colon tumors induced by AOM/DSS.

Our study provides a preclinical proof of concept to overcome resistance to immunotherapy by targeting PRMT6 in CRC with MSS.

The peremptory need to circumvent challenges associated with poorly differentiated epithelial endometrial cancers (PDEECs), also known as Type II endometrial cancers (ECs), has prompted therapeutic interrogation of the prototypically intractable and most prevalent gynecological malignancy. PDEECs account for most endometrial cancer-related mortalities due to their aggressive nature, late-stage detection, and poor response to standard therapies. PDEECs are characterized by heterogeneous histopathological features and distinct molecular profiles, and they pose significant clinical challenges due to their propensity for rapid progression. Regardless of the complexities around PDEECs, they are still being administered inefficiently in the same manner as clinically indolent and readily curable type-I ECs. Currently, there are no targeted therapies for the treatment of PDEECs. The realization of the need for new treatment options has transformed our understanding of PDEECs by enabling more precise classification based on genomic profiling. The transition from a histopathological to a molecular classification has provided critical insights into the underlying genetic and epigenetic alterations in these malignancies. This review explores the genomic landscape of PDEECs, with a focus on identifying key molecular subtypes and associated genetic mutations that are prevalent in aggressive variants. Here, we discuss how molecular classification correlates with clinical outcomes and can refine diagnostic accuracy, predict patient prognosis, and inform therapeutic strategies. Deciphering the molecular underpinnings of PDEECs has led to advances in precision oncology and protracted therapeutic remissions for patients with these untamable malignancies.

Mismatch repair (MMR) is a highly conserved, fundamental DNA damage repair pathway that maintains genomic fidelity during cell replication. MMR dysregulation contributes to tumor formation by promoting genomic instability thereby increasing the frequency of potentially oncogenic mutational events. Therefore, MMR dysregulation, in its tumor suppressor role, is largely studied in the context of genomic instability and associated response to immune checkpoint blockade therapies. However, a growing body of literature suggests that the impact of MMR dysregulation on tumor phenotypes is more nuanced than a concerted impact on genomic stability. Rather, loss of individual MMR genes promotes distinct cancer-relevant biological phenotypes, and these phenotypes are further modulated by the tissue of tumor origin. Here, we explore relevant literature and review the prognostic and predictive significance of these non-canonical discoveries.

Exonuclease 1 (EXO1) is an evolutionarily conserved exonuclease, which have function on maintaining genomic stability. Elevated expression of EXO1 has been reported in certain cancers. However, a comprehensive pan-cancer analysis of EXO1 is still lacking and its role in human cancer development remains poorly understood. This study aims to investigate the genetic alterations and expression perturbations of EXO1 and evaluate its potential clinical relevance in different cancer types. By employing powerful bioinformatics tools and utilizing data sourced from The Cancer Genome Atlas and the Genotype-Tissue Expression datasets, a comprehensive pan-cancer analysis of EXO1 was conducted, including an examination of gene expression, alterations in genetics, DNA methylation patterns, survival outcomes, clinical traits, immune features, and functional enrichment analysis. EXO1 was found to be highly expressed across 20 tumor types, including lung adenocarcinoma, lung squamous cell carcinoma, and breast invasive carcinoma. The expression levels of EXO1 are frequently associated with later clinical stages and unfavorable outcomes. Genetic alterations in EXO1 were predominantly found to be amplified in a pan-cancer context. A total of 131 missense mutations, 24 truncation mutations, 1 in-frame mutation, 6 splice site mutations, and 1 fusion mutation were identified. Interestingly, a significant co-occurrence of alterations in EXO1 with other ten gene alterations were identified. The expression of EXO1 in multiple tumors showed a significant correlation with tumor mutational burden, microsatellite instability, and genes related to immunological checkpoints. In most types of cancer, a strong correlation exists between the expression of EXO1 and the infiltration of CD4+ Th2 cells, memory CD4+ T cells, myeloid-derived suppressor cells, and common lymphoid progenitors. Analysis of 150 genes related to EXO1 demonstrate an enrichment in processes such as cell cycle regulation, DNA damage repair, and relevant signaling pathways, suggesting a possible mechanism through which EXO1 may facilitate tumor development. This study offers a deep insight into the role of EXO1 in different types of human cancers, indicating that EXO1 could act as an important prognostic biomarker and a therapeutic target for certain types of cancer.

The gut microbiota plays a crucial role in the growth performance, health status, and welfare of pigs. Breast milk is a key factor in the colonization of gut microbiota and the overall health of newborn piglets. With advancements in breeding technology, formula milk has been widely adopted as a substitute for breast milk. This study aims to investigate the effects of sow feeding (natural breastfeeding) and formula milk feeding on the gut microbiota of specific pathogen-free (SPF) Bama pigs. Using metagenomic sequencing technology, we analyzed 114 fecal samples to uncover the impacts of different feeding methods on gut microbial diversity, dominant microbial populations, metabolic functions, carbohydrate-active enzymes (CAZymes), and antibiotic resistance genes (ARGs). The results revealed significant differences in the structure and function of gut microbiota between the breast milk (BM) group and the formula milk (FM) group at day 21. The BM group exhibited higher gut microbial diversity compared to the FM group, along with more extensive metabolic functions at both the gene and species levels. Notably, the FM group demonstrated higher activity in galactose metabolism and glycan metabolism, particularly at day 21. Additionally, the FM group showed significantly higher levels of ARGs against glycopeptide antibiotics at days 21 and 28 compared to the BM group. This study also found that breastfeeding and formula feeding differentially regulate the metabolic activity of gut microbiota and the expression of related enzymes, which may have long-term effects on nutrient absorption and disease resistance in pigs. These findings provide new insights into how different feeding methods shape the gut microbiota of pigs and offer a scientific basis for optimizing feeding strategies and improving breeding efficiency.

Mismatch repair deficiency (MMR-d) and microsatellite instability (MSI) are prognostic and predictive biomarkers in oncology. Current testing for MMR/MSI relies on immunohistochemistry (IHC) for MMR proteins and molecular assays for MSI detection. This combined diagnostic strategy, however, lacks tumor specificity and does not account for gene variants. This study provides an in-depth analysis of MMR mutations frequency, spectrum, and distribution in solid tumors. Data from 23,893 patients across 11 tumor types, using 66 publicly available studies, were analyzed. MMR-mutated (MMR-m) status was defined by alterations in MLH1, PMS2, MSH2, and/or MSH6; MSI was assessed by MSIsensor. Cases with indeterminate labelling were excluded. Survival was analyzed using the Kaplan-Meier method. Among 19,353 tumors, 949 MMR variants were identified, comprising 432 pathogenic and 517 variants of unknown significance (VUS), as defined by OncoKB. MSH6 mutations were the most frequent (n = 279, 29.4 %), followed by MSH2 (n = 198, 20.9 %), MLH1 (n = 187, 19.7 %), and PMS2 (n = 161, 16.9 %). MMR-m cases were more frequent in endometrial (EC, 20.5 %), colorectal (CRC, 8.2 %), bladder (BLCA, 8.7 %), and gastroesophageal cancers (GEC, 5.4 %). Pathogenic mutations were more common than non-pathogenic in EC, CRC, and GEC (p < 0.001, p = 0.01, p = 0.32, respectively). MMR-m status was not associated with MSI in 247 (48.9 %) cases, including 67 (13.2 %) with pathogenic mutations. The highest concordance between MMR-m and MSI was observed in CRC (65.7 %), EC (91.2 %), and GEC (69.6 %), while the lowest in pancreatic (0.2 %) and lung cancers (0.1 %). MMR-m GECs showed improved overall survival compared to MMR-wt (p = 0.009), a relationship not observed in other tumor types. This study demonstrates that the MMR spectrum is extremely hetoerogeneous in solid tumors, highliting the need for comprehensive and tumor-specific testing strategies.

This review is intended to reflect the currently available literature on both clinically significant germline mutations in DNA damage repair (DDR) genes as well as the importance of ancestral diversity in the pathogenesis of prostate cancer (PCa). The second most prevalent cancer worldwide in men is PCa, causing significant morbidity and mortality in its advanced stage. Emerging data highlight the substantial role of germline mutations of DDR genes in PCa pathogenesis, especially in progression to aggressive forms of the disease. Germline genetic testing is recognized as a necessary tool for efficient, individualized patient care. NCCR guidelines recommend inquiring about the family history of PCa and known germline variants and, if indicated, proceeding with germline multigene testing followed by post-test genetic counseling. Depending on the germline mutations in HR repair genes or in MMR genes, specific treatment options may provide clinical benefit. We will discuss specific germline mutations that are involved in PCa progression and prognosis in racially diverse populations.

The prevalence of depression and anxiety is high during pregnancy. Several traditional medicines use the plant Kalanchoe pinnata (Lam.) Pers. (KP) to treat emotional disorders, inflammation, and to prevent preterm delivery, but the effects on the exposed offspring and the mechanism behind these events remain unknown.

In this work, integrated systems toxicology (INSYSTA) was used to investigate traditional toxicological outcomes and behavioral performance in zebrafish larvae after chronic exposure (from 2 to 96 hpf) to K. pinnata leaf extracts (KPL).

We investigated light/dark preference, thigmotaxis and locomotor activity parameters, followed by gene expression and systems biology approaches to discover the mechanisms behind toxicological endpoint and phenomics.

The embryos exposed to 700 mg/L KPL showed retarded development including hatching delay. Larvae exposed to 500 mg/L KPL resulted in decreased dark avoidance and increased locomotor activity, while 700 mg/L showed opposite effects. The INSYSTA revealed sixteen genes down-regulated after KPL chronic treatment; they are involved in folding, sorting, and degradation of proteins as well as DNA replication and repair mechanisms. This may result in deregulation of the organismal functions, including those of immune and endocrine systems. These physiological changes appear to make embryos more sensitive to infections and disorders that resemble 47 human diseases.

These findings suggest that the medicinal use of plant extracts requires strict toxicological, pharmacological, and medical supervision. At the same time, it suggests a polypharmacological pathway for KPL extract that goes beyond preventing premature delivery and controlling anxiety.

Ionizing radiation is mutagenic and carcinogenic, and it is reported to induce primary and secondary tumors with intestinal tumors being one of the most commonly observed. However, the pathological and molecular mechanism(s) underlying the radiation-associated tumorigenesis remain unclear. A link between radiation and somatic tumorigenesis partly through genetic, epigenetic alteration and/or regulation of mismatch repair (MMR) genes has been hypothesized for the first time within this review. Clinical observations and experimental findings provide significant support for this association including MMR mutations as well as altered MMR RNA and protein expressions that occurred post-exposure, although existing evidence in published literature is sparse in this niche area. Some speculative mechanisms are suggested with this review to inform future research. Further studies are needed to understand the roles of the MMR system in response to radiation and to test this possible connection which could potentially provide useful and urgently needed information for clinical guidance.

Mitochondrial DNA (mtDNA) mutagenesis remains poorly understood despite its crucial role in disease, aging, and evolutionary tracing. In this study, we reconstructed a comprehensive 192-component mtDNA mutational spectrum for chordates by analyzing 118,397 synonymous mutations in the CytB gene across 1,697 species and five classes. This analysis revealed three primary forces shaping mtDNA mutagenesis: (i) symmetrical, replication-driven errors by mitochondrial polymerase (POLG), resulting in C > T and A > G mutations that are highly conserved across classes; (ii) asymmetrical, damage-driven C > T mutations on the single-stranded heavy strand with clock-like dynamics; and (iii) asymmetrical A > G mutations on the heavy strand, with dynamics suggesting sensitivity to oxidative damage. The third component, sensitive to oxidative damage, positions mtDNA mutagenesis as a promising marker for metabolic and physiological processes across various classes, species, organisms, tissues, and cells. The deconvolution of the mutational spectra into mutational signatures uncovered deficiencies in both base excision repair (BER) and mismatch repair (MMR) pathways. Further analysis of mutation hotspots, abasic sites, and mutational asymmetries underscores the critical role of single-stranded DNA damage (components ii and iii), which, uncorrected due to BER and MMR deficiencies, contributes roughly as many mutations as POLG-induced errors (component i).

Arginine modification can be a "switch" to regulate DNA transcription and a post-translational modification via methylation of a variety of cellular targets involved in signal transduction, gene transcription, DNA repair, and mRNA alterations. This consequently can turn downstream biological effectors "on" and "off". Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs 1-9) in both the nucleus and cytoplasm, and is thought to be involved in many disease processes. However, PRMTs have not been well-documented in the brain and their function as it relates to metabolism, circulation, functional learning and memory are understudied. In this review, we provide a comprehensive overview of PRMTs relevant to cellular stress, and future directions into PRMTs as therapeutic regulators in brain pathologies.

The DNA damage response (DDR) and cellular metabolism exhibit a complex, bidirectional relationship crucial for maintaining genomic integrity. Studies across multiple organisms, from yeast to humans, have revealed how cells rewire their metabolism in response to DNA damage, supporting repair processes and cellular homeostasis. We discuss immediate metabolic shifts upon damage detection and long-term reprogramming for sustained genomic stability, highlighting key signaling pathways and participating molecules. Importantly, we examine how DNA repair processes can conversely induce metabolic changes and oxidative stress through specific mechanisms, including the histone H2A variant X (H2AX)/ataxia telangiectasia mutated (ATM)/NADPH oxidase 1 (Nox1) pathway and repair-specific ROS signatures. The review covers organelle-specific responses and metabolic adaptations associated with different DNA repair mechanisms, with a primary focus on human cells. We explore the implications of this DDR-metabolism crosstalk in cancer, aging, and neurodegenerative diseases, and discuss emerging therapeutic opportunities. By integrating recent findings, this review provides a comprehensive overview of the intricate interplay between DDR and cellular metabolism, offering new perspectives on cellular resilience and potential avenues for therapeutic intervention.

To assess the utility of the TCGA molecular classification of endometrial cancer in a well-annotated, moderately sized, consecutive cohort of Chinese patients with ovarian clear cell carcinoma (OCCC).

We performed DNA sequencing on 80 OCCC patients via a panel that contains 520 cancer-related genes. The TCGA molecular subtyping method was utilized for classification. The clinicopathological features were analysed, and the survival correlation was assessed for each subtype.

The most common mutated genes were ARID1A (49%) and PIK3CA (48%). No pathogenic POLE mutations were detected. MSI-high (MSI-H) tumours were observed in 5 (6.3%) patients. A total of 16.3% (13/80) of the patients were classified as the p53 abnormal (p53abn) subtype, and 77.5% (62/80) were classified as the nonspecific molecular profile (NSMP) subtype. All the MSI-H patients had ARID1A mutations, whereas patients with the p53abn subtype had the lowest percentage of ARID1A mutations (27.3%). No significant differences were observed between the molecular subtypes and clinicopathological features. The progression-free survival and overall survival of the entire cohort were closely associated with FIGO stage (p < 0.01), the presence of residual tumour (p < 0.01), and the platinum response (p < 0.01). Molecular classification did not significantly impact prognosis. Univariate analysis revealed that TP53 mutations in advanced-stage (FIGO III-IV) patients were associated with shorter survival.

We did not find prognostic significance of TCGA molecular subtyping in OCCC. POLEmuts are extremely rare, and the incidence of MSI-H and p53abn tumours is also quite low. Further subtyping of the NSMP subgroup is warranted.

The molecular basis of adaptive evolution and cancer progression are both complex processes that share many striking similarities. The potential adaptive significance of environmentally-induced epigenetic changes is currently an area of great interest in both evolutionary and cancer biology. In the field of cancer biology intense effort has been focused on the contribution of stress-induced non-coding RNAs (ncRNAs) in the activation of epigenetic changes associated with elevated mutation rates and the acquisition of environmentally adaptive traits. Examples of this process are presented and combined with more recent findings demonstrating that stress-induced ncRNAs are transferable from somatic to germline cells leading to cross-generational inheritance of acquired adaptive traits. The fact that ncRNAs have been implicated in the transient adaptive response of various plants and animals to environmental stress is consistent with findings in cancer biology. Based on these collective observations, a general model as well as specific and testable hypotheses are proposed on how transient ncRNA-mediated adaptive responses may facilitate the transition to long-term biological adaptation in both cancer and evolution.

The [4Fe-4S] cluster is an important cofactor of the base excision repair (BER) adenine DNA glycosylase MutY to prevent mutations associated with 8-oxoguanine (OG). Several MutYs lacking the [4Fe-4S] cofactor have been identified. Phylogenetic analysis shows that clusterless MutYs are distributed in two clades suggesting cofactor loss in two independent evolutionary events. Herein, we determined the first crystal structure of a clusterless MutY complexed with DNA. On the basis of the dramatic structural divergence from canonical MutYs, we refer to this as representative of a clusterless MutY subgroup "MutYX". Interestingly, MutYX compensates for the missing [4Fe-4S] cofactor to maintain positioning of catalytic residues by expanding a pre-existing α-helix and acquisition of the new α-helix. Surprisingly, MutYX also acquired a new C-terminal domain that uniquely recognizes OG using residue Gln201 and Arg209. Adenine glycosylase assays and binding affinity measurements indicate that Arg209 is the primary residue responsible to specificity for OG:A lesions, while Gln201 bridges OG and Arg209. Surprisingly, replacement of Arg209 and Gln201 with Ala increases activity toward G:A mismatches. The MutYX structure serves as an example of devolution, capturing structural features required to retain function in the absence of a metal cofactor considered indispensable.

Most giant viruses including Mimiviridae family build large viral factories within the host cytoplasms. These giant viruses are presumed to possess specific genes that enable the rapid and massive replication of their large double-stranded DNA genomes within viral factories. It has been revealed that a functionally uncharacterized protein, MutS7, is expressed during the operational phase of the viral factory. MutS7 contains an N-terminal mismatched DNA-binding domain, which is similar to the mismatched DNA-recognizing protein MutS1, and a unique C-terminal HNH endonuclease domain absent in other MutS family proteins. MutS7 gene of the genus Mimivirus of the family Mimiviridae is encoded in the locus that is responsible for resistance against infection of a virophage. In the present study, we characterized the MutS7 HNH domain of Mimivirus shirakomae. The HNH domain preferentially bound to branched DNA structures containing single-stranded regions, especially the displacement-loop structure, which is a primary intermediate in homologous/homeologous recombination, rather than to linear DNAs and branched DNAs lacking single-stranded regions. However, the HNH domain exhibited no endonuclease activity. The site-directed mutagenesis analysis revealed that the Cys4-type zinc finger of the HNH domain was not essential, but was important for the DNA binding. Given that giant virus MutS7 contains a mismatch-binding domain in addition to the HNH domain, we propose that giant virus MutS7 may suppress homeologous recombination in the viral factory.

Nucleic acids are highly charged, and electrical forces are involved heavily in how our DNA is compacted and packaged into such a small space, how chromosomes are formed, and how DNA damage is repaired. In addition, electrical forces are crucial to the formation of non-canonical DNA structures called G-Quadruplexes which play multiple biological roles.

Replication Protein A (RPA) plays a pivotal role in DNA replication by coating and protecting exposed single-stranded DNA, and acting as a molecular hub that recruits additional replication factors. We demonstrate that archaeal RPA hosts a winged-helix domain (WH) that interacts with two key actors of the replisome: the DNA primase (PriSL) and the replicative DNA polymerase (PolD). Using an integrative structural biology approach, combining nuclear magnetic resonance, X-ray crystallography and cryo-electron microscopy, we unveil how RPA interacts with PriSL and PolD through two distinct surfaces of the WH domain: an evolutionarily conserved interface and a novel binding site. Finally, RPA is shown to stimulate the activity of PriSL in a WH-dependent manner. This study provides a molecular understanding of the WH-mediated regulatory activity in central replication factors such as RPA, which regulate genome maintenance in Archaea and Eukaryotes.

Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract, it is known as the "silent killer", which poses a serious threat to the lives of patients. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway responds to DNA by sensing, which plays an important role in anti-infection, autoimmune diseases and anti-tumor immunity. Recent studies have found that the activation of cGAS-STING pathway in CRC can induce the expression and secretion of type I interferon (IFN-I) and a variety of inflammatory factors, further activate anti-tumor CD8+ T cells, exert anti-tumor immune response, and inhibit the progression of CRC. Therefore, targeting the cGAS-STING pathway and developing drugs that can regulate the cGAS-STING pathway are of great significance for improving the therapeutic effect and prognosis of CRC patients. In this review, we introduce the cGAS-STING signaling pathway and the regulatory role of this signaling pathway in CRC immune microenvironment. In addition, we discussed the research progress of cGAS-STING pathway in CRC immunotherapy and the clinical research status of STING agonists developed against this pathway, emphasizing the clinical potential of CRC immunotherapy based on the cGAS-STING signaling pathway.

DNA repair systems are essential to maintain genome integrity and stability. Some obligate endosymbionts that experience long-term symbiosis with the insect hosts, however, have lost their key components for DNA repair. It is largely unexplored how the bacterial endosymbionts cope with the increased demand for mismatch repairs under heat stresses. Here, we showed that ibpA, a small heat shock protein encoded by Buchnera aphidicola, directly interacted with the cytoskeletal actin to prevent its aggregation in bacteriocytes, thus reinforcing the stability of bacteriocytes. However, the succession of 11 adenines in the promoter of ibpA is extremely prone to mismatching error, e.g., a single adenine deletion, which impairs the induction of ibpA under heat stress. Coinfection with a facultative endosymbiont Serratia symbiotica remarkably reduced the mutagenesis rate in the Buchnera genome and potentially prevented a single adenine deletion in ibpA promoter, thereby alleviating the heat vulnerability of aphid bacteriocytes. Furthermore, Serratia encoded mutH, a conserved core protein of prokaryotic DNA mismatch repair (MMR), accessed to Buchnera cells, which complemented Buchnera mutL and mutS in constituting an active MMR. Our findings imply that a full complement of a prokaryotic MMR system assembled by two bacterial endosymbionts contributes significantly to the thermostability of aphid bacteriocytes in an ibpA-dependent manner, furnishing a distinct molecular link among tripartite symbioses in shaping resilience and adaptation of their insect hosts to occupy other ecological niches.

The environmental use of azole fungicides has led to selective sweeps across multiple loci in the Aspergillus fumigatus genome causing the rapid global expansion of a genetically distinct cluster of resistant genotypes. Isolates within this cluster are also more likely to be resistant to agricultural antifungals with unrelated modes of action. Here we show that this cluster is not only multi-azole resistant but has increased propensity to develop resistance to next generation antifungals because of variants in the DNA mismatch repair system. A variant in msh6-G233A is found almost exclusively within azole resistant isolates harbouring the canonical cyp51A azole resistance allelic variant TR34/L98H. Naturally occurring isolates with this msh6 variant display up to 5-times higher rate of mutation, leading to an increased likelihood of evolving resistance to other antifungals. Furthermore, unlike hypermutator strains, the G233A variant conveys no measurable fitness cost and has become globally distributed. Our findings further suggest that resistance to next-generation antifungals is more likely to emerge within organisms that are already multi-azole resistant due to close linkage between TR34/L98H and msh6-G233A, posing a major problem due to the prospect of dual use of novel antifungals in clinical and agricultural settings.

TAF1L may play an important role in the occurrence and development of gastric cancer (GC), but the correlation between the expression of TAF1L and the clinicopathological factors and prognosis of GC is still unclear.

A total of 1053 GC patients in Zhejiang Cancer Hospital between January 1st, 2018 to December 31th, 2019 were screened. Finally, 120 patients met the inclusion criteria. TAF1L expression was detected by immunohistochemistry, and the correlations of TAF1L in clinicopathological characteristics and prognosis were analyzed. TCGA GC dataset was used to perform further bioinformatics analysis.

In this study, TAF1L expression was evaluated in 120 clinical samples of GC. TAF1L expression was higher in tumor tissues and was associated with tumor differentiation (p = 0.046), signet-ring cells (p = 0.043), dMMR status (p = 0.011), lympho-vascular invasion (p = 0.038), and neural invasion (p = 0.005) in our cohort. Cases with high expression of TAF1L presented worse mean OS than those with low expression (40.3 months vs. 51.8 months, p = 0.019), and the difference was also significant in HER2-positive cases (20.9 months vs. 51.2 months, p = 0.007) as well as pMMR cases (38.8 months vs. 51.6 months, p = 0.006). Multivariate Cox regression analysis showed that TAF1L (HR = 2.044, 95%CI = 1.007-4.147, p = 0.048) and HER2 status (HR = 2.383, 95%CI = 1.087-5.222, p = 0.030) were independent prognosis factors of these patients. In subgroup analysis, TAF1L was the independent prognostic risk factor in HER2-positive patients (HR = 6.736, 95%CI = 1.373-33.032, p = 0.019). and pMMR patients (HR = 2.291, 95%CI = 1.126-4.660, p = 0.022). Besides, HER2 status was the independent prognostic risk factor in TAF1L-H patients (HR = 4.832, 95%CI = 1.908-12.239, p = 0.001). TCGA dataset also indicated the higher expression of TAF1L in tumors than normal tissues (p < 0.001). High TAF1L expression is linked to worse survival in MSS (11.0 months vs. 35.0 months, p = 0.0046) groups, and is negatively associated with overall survival in HER2-positive cases (24.0 months vs. 57.0 months, p = 0.0039).

TAF1L is closely related to the occurrence and development of GC. Our results suggested that TAF1L is a significant biomarker for predicting prognosis of GC and may play an important role in immunotherapy and targeted therapy.

Using transient inhibition of DNA mismatch repair during a permissive stage of development, we demonstrate highly efficient prime editing of mouse embryos with few unwanted, local byproducts (average 58% precise edit frequency, 0.5% on-target error frequency across 13 substitution edits at 8 sites), enabling same-generation phenotyping of founders. Whole-genome sequencing reveals that mismatch repair inhibition increases off-target indels at low-complexity regions in the genome without any obvious phenotype in mice.

Non-coding CGG repeat expansions within the 5' untranslated region are implicated in a range of neurological disorders, including fragile X-associated tremor/ataxia syndrome, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. This review outlined the general characteristics of diseases associated with non-coding CGG repeat expansions, detailing their clinical manifestations and neuroimaging patterns, which often overlap and indicate shared pathophysiological traits. We summarized the underlying molecular mechanisms of these disorders, providing new insights into the roles that DNA, RNA, and toxic proteins play. Understanding these mechanisms is crucial for the development of targeted therapeutic strategies. These strategies include a range of approaches, such as antisense oligonucleotides, RNA interference, genomic DNA editing, small molecule interventions, and other treatments aimed at correcting the dysregulated processes inherent in these disorders. A deeper understanding of the shared mechanisms among non-coding CGG repeat expansion disorders may hold the potential to catalyze the development of innovative therapies, ultimately offering relief to individuals grappling with these debilitating neurological conditions.

Endometrial cancer is one of the most common gynecological malignancies, and while early-stage cases are highly treatable, recurrent or advanced EC remains challenging to manage. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized treatment approaches in oncology, and its application in EC has shown promising results. Key to immunotherapy efficacy in EC is the tumor's mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. However, not all mismatch repair-deficient (MMRd) tumors respond to ICIs, particularly those with a "cold" tumor microenvironment (TME) characterized by poor immune infiltration. In contrast, some MMR-proficient tumors with a "hot" TME respond well to ICIs, underscoring the complex interplay between MMR status, tumor mutational burden (TMB), and TME. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.

Around the world, oral cancer (OC) is a major public health problem, resulting in a significant number of deaths each year. Early detection and treatment are crucial for improving patient outcomes. Recent progress in DNA sequencing and transcriptome profiling has revealed extensive non-coding RNAs (ncRNAs) transcription, underscoring their regulatory importance. NcRNAs influence genomic transcription and translation and molecular signaling pathways, making them valuable for various clinical applications. Combining spatial transcriptomics (ST) and spatial metabolomics (SM) with single-cell RNA sequencing provides deeper insights into tumor microenvironments, enhancing diagnostic and therapeutic precision for OC. Additionally, the exploration of salivary biomarkers offers a non-invasive diagnostic avenue. This article explores the potential of ncRNAs as diagnostic and therapeutic tools for OC.

The propensity of humans and non-human animals to discount future returns for short-term benefits is well established. This contrasts with the ability of organisms to unfold complex developmental sequences over months or years efficiently. Research has focused on various descriptive and predictive parameters of 'temporal discounting' in behavior, and researchers have proposed models to explain temporal preference in terms of fitness-maximizing outcomes. Still, the underlying ultimate cause of this phenomenon has not been deeply explored across taxa. Here, we propose an ultimate (i.e., evolutionary) causal explanation for the selection of temporal discounting largely conserved across taxa. We propose that preference for a short-term reward (e.g., heightened impulsivity) often is less than optimal and likely is the product of constraints imposed on natural selection with respect to predicting events in a temporal framework in the context of future uncertainty. Using a simple Newtonian model for time across a fitness landscape in which movement by organisms is only possible in one direction, we examine several factors that influence the ability of an organism to choose a distant reward over a more temporally proximate reward: including the temporal distance of the far reward, the relative value of the distant reward, and the effect of uncertainty about the value and presence of the distant reward. Our results indicate that an organism may choose a more distant reward, but only if it is not too far into the future and has a substantially higher-value fitness payoff relative to the short-term reward. Notably, any uncertainty about the distant reward made it extremely unlikely for an organism to choose the delayed reward strategy compared to choosing a closer reward, even if the distant reward had a much higher payoff because events that are uncertain are only partially visible to natural selection pressures. The results help explain why natural selection is constrained to promote more optimal behavioral strategies and why it has difficulty selecting a distant reward over a lower-value short-term reward. The degree of uncertainty is an especially salient ecological variable in promoting and preferencing short-term behavioral strategies across taxa. These results further help illustrate why, from an ultimate causal perspective, human and non-human taxa have difficulty making more optimal long-term decisions.

TAR DNA-binding protein 43 (TDP43) is increasingly recognized for its involvement in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 proteinopathy, characterized by dysregulated nuclear export and cytoplasmic aggregation, is present in most ALS/FTD cases and is associated with a loss of nuclear function and genomic instability in neurons. Building on prior evidence linking TDP43 pathology to DNA double-strand breaks (DSBs), this study identifies a novel regulatory role for TDP43 in the DNA mismatch repair (MMR) pathway. We demonstrate that depletion or overexpression of TDP43 affects the expression of key MMR genes, including MLH1, MSH6, MSH2, MSH3, and PMS2. Specifically, TDP43 modulates the expression of MLH1 and MSH6 proteins through alternative splicing and transcript stability. These findings are validated in ALS mice models, patient-derived neural progenitor cells and autopsied brain tissues from ALS patients. Furthermore, MMR depletion showed a partial rescue of TDP43-induced DNA damage in neuronal cells. Bioinformatics analysis of TCGA cancer database reveals significant correlations between TDP43 and MMR gene expressions and mutational burden across various cancer subtypes. These results collectively establish TDP43 as a critical regulator of the MMR pathway, with broad implications for understanding the genomic instability underlying neurodegenerative and neoplastic diseases.

Whole-genome sequencing studies of parent-offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.

Lung carcinoids (L-CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L-CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L-CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole-exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L-CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L-CD-PanC and L-CD-NeU. L-CD-PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion (p < 1 × 10-6). These tumours were centrally located and showed mutational signatures of activation-induced deaminase/apolipoprotein B editing complex  activity, together with genome-wide DNA methylation loss enriched in repetitive elements (p = 2.2 × 10-16). By contrast, the L-CD-NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology (p = 0.04), peripheral location (p = 0.01), high mutational load (p = 2.17 × 10-4), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L-CD-NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid (p = 0.05), suggesting a possible environmental exposure in their pathogenesis. Immunologically, myeloid and T-cell markers were enriched in L-CD-PanC and B-cell markers in L-CD-NeU tumours. The substantial epigenetic and non-coding differences between L-CD-PanC and L-CD-NeU open new possibilities for biomarker selection and targeted treatment of L-CD. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Nonstop extension mutations, a.k.a. stop-lost or stop-loss mutations, convert a stop codon into a sense codon resulting in translation into the 3' untranslated region until the next in-frame stop codon, thereby extending the C-terminus of a protein. In cancer, only nonstop mutations in SMAD4 have been functionally characterized, while the impact of other nonstop mutations remain unknown. Here, we exploit our pan-cancer NonStopDB dataset and test all 2335 C-terminal extensions arising from somatic nonstop mutations in cancer for their impact on protein expression. In a high-throughput screen, 56.1% of the extensions effectively reduce protein abundance. Extensions of multiple tumor suppressor genes like PTEN, APC, B2M, CASP8, CDKN1B and MLH1 are effective and validated for their suppressive impact. Importantly, the effective extensions possess a higher hydrophobicity than the neutral extensions linking C-terminal hydrophobicity with protein destabilization. Analyzing the proteomes of eleven different species reveals conserved patterns of amino acid distribution in the C-terminal regions of all proteins compared to the proteomes like an enrichment of lysine and arginine and a depletion of glycine, leucine, valine and isoleucine across species and kingdoms. These evolutionary selection patterns are disrupted in the cancer-derived effective nonstop extensions.