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Merrick BA, Brooks AM, Foley JF, Martin NP, Fannin RD, Gladwell W, Gerrish KE. hTERT and SV40LgT Renal Cell Lines Adjust Their Transcriptional Responses After Copy Number Changes from the Parent Proximal Tubule Cells. Int J Mol Sci 2025; 26:3607. [PMID: 40332109 PMCID: PMC12027150 DOI: 10.3390/ijms26083607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Primary mouse renal proximal tubule epithelial cells (moRPTECs) were immortalized by lentivirus transduction to create hTERT or SV40LgT (LgT) cell lines. Prior work showed a more pronounced injury and repair response in LgT versus hTERT cells after chemical challenge. We hypothesized that unique genomic changes occurred after immortalization, altering critical genes and pathways. RNA-seq profiling and whole-genome sequencing (WGS) of parent, hTERT, and LgT cells showed that 92.5% of the annotated transcripts were shared, suggesting a conserved proximal tubule expression pattern. However, the cell lines exhibited unique transcriptomic and genomic profiles different from the parent cells. Three transcript classes were quite relevant for chemical challenge response-Cyps, ion channels, and metabolic transporters-each important for renal function. A pathway analysis of the hTERT cells suggested alterations in intermediary and energy metabolism. LgT cells exhibited pathway activation in cell cycle and DNA repair that was consistent with replication stress. Genomic karyotyping by combining WGS and RNA-seq data showed increased gene copy numbers in chromosome 5 for LgT cells, while hTERT cells displayed gene copy losses in chromosomes 4 and 9. These data suggest that the exaggerated transcriptional responses of LgT cells versus hTERT cells result from differences in gene copy numbers, replication stress, and the unique selection processes underlying LgT or hTERT immortalization.
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Affiliation(s)
- Bruce Alex Merrick
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA;
| | - Ashley M. Brooks
- Biostatistics and Computational Biology Branch, Integrative Bioinformatics Support Group, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA;
| | - Julie F. Foley
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA;
| | - Negin P. Martin
- Viral Vector Core, Neurobiology Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA;
| | - Rick D. Fannin
- Molecular Genomics Core Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA; (R.D.F.); (W.G.); (K.E.G.)
| | - Wesley Gladwell
- Molecular Genomics Core Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA; (R.D.F.); (W.G.); (K.E.G.)
| | - Kevin E. Gerrish
- Molecular Genomics Core Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA; (R.D.F.); (W.G.); (K.E.G.)
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Nickoloff JA. Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy. Molecules 2022; 27:4736. [PMID: 35897913 PMCID: PMC9330692 DOI: 10.3390/molecules27154736] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 12/12/2022] Open
Abstract
Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.
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Affiliation(s)
- Jac A Nickoloff
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Nickoloff JA, Sharma N, Allen CP, Taylor L, Allen SJ, Jaiswal AS, Hromas R. Roles of homologous recombination in response to ionizing radiation-induced DNA damage. Int J Radiat Biol 2021; 99:903-914. [PMID: 34283012 PMCID: PMC9629169 DOI: 10.1080/09553002.2021.1956001] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/04/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Ionizing radiation induces a vast array of DNA lesions including base damage, and single- and double-strand breaks (SSB, DSB). DSBs are among the most cytotoxic lesions, and mis-repair causes small- and large-scale genome alterations that can contribute to carcinogenesis. Indeed, ionizing radiation is a 'complete' carcinogen. DSBs arise immediately after irradiation, termed 'frank DSBs,' as well as several hours later in a replication-dependent manner, termed 'secondary' or 'replication-dependent DSBs. DSBs resulting from replication fork collapse are single-ended and thus pose a distinct problem from two-ended, frank DSBs. DSBs are repaired by error-prone nonhomologous end-joining (NHEJ), or generally error-free homologous recombination (HR), each with sub-pathways. Clarifying how these pathways operate in normal and tumor cells is critical to increasing tumor control and minimizing side effects during radiotherapy. CONCLUSIONS The choice between NHEJ and HR is regulated during the cell cycle and by other factors. DSB repair pathways are major contributors to cell survival after ionizing radiation, including tumor-resistance to radiotherapy. Several nucleases are important for HR-mediated repair of replication-dependent DSBs and thus replication fork restart. These include three structure-specific nucleases, the 3' MUS81 nuclease, and two 5' nucleases, EEPD1 and Metnase, as well as three end-resection nucleases, MRE11, EXO1, and DNA2. The three structure-specific nucleases evolved at very different times, suggesting incremental acceleration of replication fork restart to limit toxic HR intermediates and genome instability as genomes increased in size during evolution, including the gain of large numbers of HR-prone repetitive elements. Ionizing radiation also induces delayed effects, observed days to weeks after exposure, including delayed cell death and delayed HR. In this review we highlight the roles of HR in cellular responses to ionizing radiation, and discuss the importance of HR as an exploitable target for cancer radiotherapy.
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Affiliation(s)
- Jac A. Nickoloff
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Neelam Sharma
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Christopher P. Allen
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
- Department of Microbiology, Immunology and Pathology, Flow Cytometry and Cell Sorting Facility, Colorado State University, Fort Collins, CO, USA
| | - Lynn Taylor
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Sage J. Allen
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Aruna S. Jaiswal
- Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA
| | - Robert Hromas
- Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA
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Chai S, Tian R, Bi J, Xu S, Yang G, Ren W. Rapid evolution and molecular convergence in cryptorchidism-related genes associated with inherently undescended testes in mammals. BMC Ecol Evol 2021; 21:22. [PMID: 33568072 PMCID: PMC7877101 DOI: 10.1186/s12862-021-01753-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 01/28/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The mammalian testis is an important male exocrine gland and spermatozoa-producing organ that usually lies in extra-abdominal scrotums to provide a cooler environment for spermatogenesis and sperm storage. Testicles sometimes fail to descend, leading to cryptorchidism. However, certain groups of mammals possess inherently ascrotal testes (i.e. testes that do not descend completely or at all) that have the same physiological functions as completely descended scrotal testes. Although several anatomical and hormonal factors involved in testicular descent have been studied, there is still a paucity of comprehensive research on the genetic mechanisms underlying the evolution of testicular descent in mammals and how mammals with ascrotal testes maintain their reproductive health. RESULTS We performed integrative phenotypic and comparative genomic analyses of 380 cryptorchidism-related genes and found that the mammalian ascrotal testes trait is derived from an ancestral scrotal state. Rapidly evolving genes in ascrotal mammals were enriched in the Hedgehog pathway-which regulates Leydig cell differentiation and testosterone secretion-and muscle development. Moreover, some cryptorchidism-related genes in ascrotal mammals had undergone positive selection and contained specific mutations and indels. Genes harboring convergent/parallel amino acid substitutions between ascrotal mammals were enriched in GTPase functions. CONCLUSIONS Our results suggest that the scrotal testis is an ancestral state in mammals, and the ascrotal phenotype was derived multiple times in independent lineages. In addition, the adaptive evolution of genes involved in testicular descent and the development of the gubernaculum contributed to the evolution of ascrotal testes. Accurate DNA replication, the proper segregation of genetic material, and appropriate autophagy are the potential mechanisms for maintaining physiological normality during spermatogenesis in ascrotal mammals. Furthermore, the molecular convergence of GTPases is probably a mechanism in the ascrotal testes of different mammals. This study provides novel insights into the evolution of the testis and scrotum in mammals and contributes to a better understanding of the pathogenesis of cryptorchidism in humans.
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Affiliation(s)
- Simin Chai
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Ran Tian
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Juanjuan Bi
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Shixia Xu
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China
| | - Guang Yang
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China.
| | - Wenhua Ren
- School of Life Sciences, Nanjing Normal University, Nanjing, 210023, Jiangsu, China.
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Albers E, Avram A, Sbroggio M, Fernandez-Capetillo O, Lopez-Contreras AJ. Supraphysiological protection from replication stress does not extend mammalian lifespan. Aging (Albany NY) 2020; 12:5612-5624. [PMID: 32253367 PMCID: PMC7185120 DOI: 10.18632/aging.103039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/10/2020] [Indexed: 12/05/2022]
Abstract
Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATR-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas- irrespective of their genetic background. Interestingly, a higher but not statistically significant percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of normal aging.
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Affiliation(s)
- Eliene Albers
- Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Alexandra Avram
- Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Mauro Sbroggio
- Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | | | - Andres J Lopez-Contreras
- Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
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7
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Azenha D, Lopes MC, Martins TC. Claspin: From replication stress and DNA damage responses to cancer therapy. DNA Repair (Amst) 2019; 115:203-246. [DOI: 10.1016/bs.apcsb.2018.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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8
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Villa M, Bonetti D, Carraro M, Longhese MP. Rad9/53BP1 protects stalled replication forks from degradation in Mec1/ATR-defective cells. EMBO Rep 2018; 19:351-367. [PMID: 29301856 PMCID: PMC5797966 DOI: 10.15252/embr.201744910] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/29/2017] [Accepted: 12/08/2017] [Indexed: 12/16/2022] Open
Abstract
Nucleolytic processing by nucleases can be a relevant mechanism to allow repair/restart of stalled replication forks. However, nuclease action needs to be controlled to prevent overprocessing of damaged replication forks that can be detrimental to genome stability. The checkpoint protein Rad9/53BP1 is known to limit nucleolytic degradation (resection) of DNA double-strand breaks (DSBs) in both yeast and mammals. Here, we show that loss of the inhibition that Rad9 exerts on resection exacerbates the sensitivity to replication stress of Mec1/ATR-defective yeast cells by exposing stalled replication forks to Dna2-dependent degradation. This Rad9 protective function is independent of checkpoint activation and relies mainly on Rad9-Dpb11 interaction. We propose that Rad9/53BP1 supports cell viability by protecting stalled replication forks from extensive resection when the intra-S checkpoint is not fully functional.
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Affiliation(s)
- Matteo Villa
- Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy
| | - Diego Bonetti
- Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy
| | - Massimo Carraro
- Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy
| | - Maria Pia Longhese
- Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy
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9
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Boulianne B, Feldhahn N. Transcribing malignancy: transcription-associated genomic instability in cancer. Oncogene 2017; 37:971-981. [DOI: 10.1038/onc.2017.402] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/12/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022]
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10
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Lu D, Luo P, Wang Q, Ye Y, Wang B. lncRNA PVT1 in cancer: A review and meta-analysis. Clin Chim Acta 2017; 474:1-7. [DOI: 10.1016/j.cca.2017.08.038] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 08/21/2017] [Accepted: 08/25/2017] [Indexed: 01/11/2023]
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11
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Cui X, Jing X, Long C, Tian J, Zhu J. Long noncoding RNA MEG3, a potential novel biomarker to predict the clinical outcome of cancer patients: a meta-analysis. Oncotarget 2017; 8:19049-19056. [PMID: 28157702 PMCID: PMC5386668 DOI: 10.18632/oncotarget.14987] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 01/11/2017] [Indexed: 12/12/2022] Open
Abstract
Numerous studies have demonstrated that the expression level of maternally expressed gene 3 (MEG3) was lost in various cancers. Low expression of MEG3 is associated with an increased risk of metastasis and a poor prognosis in cancer patients. This meta-analysis investigated the association between MEG3 levels and distant metastasis (DM), lymph node metastasis (LNM), overall survival (OS), and recurrence-free survival (RFS) of cancer patients. A total of 536 participants from 9 articles were finally enrolled. The results showed a significant negative association between MEG3 levels and DM (OR = 2.16, 95% CI = 0.99–4.71, P = 0.05, fixed-effect), and it could also predict poor OS (HR = 0.43, 95% CI = 0.15–1.24, P = 0.006, fixed-effect) and RFS (HR = 0.52, 95% CI = 0.29–0.92, P = 0.02, fixed-effect) in cancer patients. In conclusion, this meta-analysis indicated that MEG3 might serve as a potential novel biomarker for indicating the clinical outcomes in human cancers.
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Affiliation(s)
- Xiangrong Cui
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Xuan Jing
- Clinical Laboratory, Shanxi Province People's Hospital, Shanxi, 030000, China
| | - Chunlan Long
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Jie Tian
- Cardiovascular Department (Internal Medicine), Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Jing Zhu
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
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12
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Blumenfeld B, Ben-Zimra M, Simon I. Perturbations in the Replication Program Contribute to Genomic Instability in Cancer. Int J Mol Sci 2017; 18:E1138. [PMID: 28587102 PMCID: PMC5485962 DOI: 10.3390/ijms18061138] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 05/08/2017] [Accepted: 05/21/2017] [Indexed: 12/14/2022] Open
Abstract
Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program.
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Affiliation(s)
- Britny Blumenfeld
- Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
| | - Micha Ben-Zimra
- Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
- Pharmacology and Experimental Therapeutics Unit, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
| | - Itamar Simon
- Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
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