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Mutagenesis Feb 2020Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient... (Review)
Review
Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient outcome. Hypoxia also contributes to genomic instability and mutation frequency by inhibiting DNA repair pathways. This review summarises the diverse mechanisms by which hypoxia affects DNA repair, including suppression of homology-directed repair, mismatch repair and base excision repair. We also discuss the effects of hypoxia mimetics and agents that induce hypoxia on DNA repair, and we highlight areas of potential clinical relevance as well as future directions.
Topics: Cell Hypoxia; DNA Mismatch Repair; DNA Repair; Gene Expression Regulation, Neoplastic; Genome; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; Recombinational DNA Repair; Tumor Hypoxia; Tumor Microenvironment
PubMed: 31282537
DOI: 10.1093/mutage/gez019 -
Journal of Biomolecular Screening Aug 2015Genomic DNA is constantly exposed to endogenous and exogenous damaging agents. To overcome these damaging effects and maintain genomic stability, cells have robust... (Review)
Review
Genomic DNA is constantly exposed to endogenous and exogenous damaging agents. To overcome these damaging effects and maintain genomic stability, cells have robust coping mechanisms in place, including repair of the damaged DNA. There are a number of DNA repair pathways available to cells dependent on the type of damage induced. The removal of damaged DNA is essential to allow successful repair. Removal of DNA strands is achieved by nucleases. Exonucleases are those that progressively cut from DNA ends, and endonucleases make single incisions within strands of DNA. This review focuses on the group of endonucleases involved in DNA repair pathways, their mechanistic functions, roles in cancer development, and how targeting these enzymes is proving to be an exciting new strategy for personalized therapy in cancer.
Topics: Biomarkers; DNA Damage; DNA Repair; Endonucleases; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Prognosis
PubMed: 25877151
DOI: 10.1177/1087057115581581 -
Antioxidants & Redox Signaling May 2021Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased... (Review)
Review
Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Genomic stress is closely intertwined with antitumor immunity mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. 34, 1128-1150.
Topics: DNA Damage; DNA Repair; Genome, Human; Genomic Instability; Genomics; Humans; Immunity, Innate; Neoplasms; Tumor Microenvironment
PubMed: 33143450
DOI: 10.1089/ars.2020.8221 -
Mutation Research. Reviews in Mutation... 2015Oxidatively induced DNA damage is caused in living organisms by endogenous and exogenous reactive species. DNA lesions resulting from this type of damage are mutagenic... (Review)
Review
Oxidatively induced DNA damage is caused in living organisms by endogenous and exogenous reactive species. DNA lesions resulting from this type of damage are mutagenic and cytotoxic and, if not repaired, can cause genetic instability that may lead to disease processes including carcinogenesis. Living organisms possess DNA repair mechanisms that include a variety of pathways to repair multiple DNA lesions. Mutations and polymorphisms also occur in DNA repair genes adversely affecting DNA repair systems. Cancer tissues overexpress DNA repair proteins and thus develop greater DNA repair capacity than normal tissues. Increased DNA repair in tumors that removes DNA lesions before they become toxic is a major mechanism for development of resistance to therapy, affecting patient survival. Accumulated evidence suggests that DNA repair capacity may be a predictive biomarker for patient response to therapy. Thus, knowledge of DNA protein expressions in normal and cancerous tissues may help predict and guide development of treatments and yield the best therapeutic response. DNA repair proteins constitute targets for inhibitors to overcome the resistance of tumors to therapy. Inhibitors of DNA repair for combination therapy or as single agents for monotherapy may help selectively kill tumors, potentially leading to personalized therapy. Numerous inhibitors have been developed and are being tested in clinical trials. The efficacy of some inhibitors in therapy has been demonstrated in patients. Further development of inhibitors of DNA repair proteins is globally underway to help eradicate cancer.
Topics: DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasms; Oxidative Stress
PubMed: 25795122
DOI: 10.1016/j.mrrev.2014.11.002 -
Genes Jun 2023Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Topics: Humans; DNA Repair; DNA Damage; Genomic Instability
PubMed: 37510290
DOI: 10.3390/genes14071385 -
Clinical Cancer Research : An Official... Dec 2016Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in... (Review)
Review
Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651-60. ©2016 AACR.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA Repair; Drug Resistance, Neoplasm; Humans; Mutation; Neoplasms
PubMed: 27678458
DOI: 10.1158/1078-0432.CCR-16-0247 -
Cell Reports Mar 2022BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but...
BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.
Topics: Body Mass Index; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Endodeoxyribonucleases; Homologous Recombination; Recombinational DNA Repair
PubMed: 35320715
DOI: 10.1016/j.celrep.2022.110536 -
International Journal of Biological... 2017One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand... (Review)
Review
One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand DNA, thus decreasing the chances of generating double-strand breaks in the genome. Therefore, the concept to block PARP enzymes by PARP inhibitor (PARPi) was appreciated in cancer treatment. PARPi has been designed and tested for many years and became a potential supplement for the conventional chemotherapy. However, increasing evidence indicates the appearance of the resistance to this treatment. Specifically, cancer cells may acquire new mutations or events that overcome the positive effect of these drugs. This paper describes several molecular mechanisms of PARPi resistance which were reported most recently, and summarizes some strategies to reverse this type of drug resistance.
Topics: Animals; BRCA1 Protein; DNA Repair; Drug Resistance, Neoplasm; Humans; MicroRNAs; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 28255272
DOI: 10.7150/ijbs.17240 -
Cell Death & Disease Nov 2023DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired... (Review)
Review
DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). To repair DSBs, a large amount of DNA repair factors was observed to be concentrated at the end of DSBs in a specific spatiotemporal manner to form a repair center. Recently, this repair center was characterized as a condensate derived from liquid-liquid phase separation (LLPS) of key DSBs repair factors. LLPS has been found to be the mechanism of membraneless organelles formation and plays key roles in a variety of biological processes. In this review, the recent advances and mechanisms of LLPS in the formation of DSBs repair-related condensates are summarized.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; DNA Damage; DNA
PubMed: 37968256
DOI: 10.1038/s41419-023-06267-0 -
BioEssays : News and Reviews in... May 2018The repair of chromosomal double-strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the... (Review)
Review
The repair of chromosomal double-strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the RecA/Rad51-mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template to repair the lesion. Here, in reviewing research about DSB repair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination mechanisms. See also the video abstract here: https://youtu.be/vm7-X5uIzS8.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; Humans; Rad51 Recombinase; Rec A Recombinases; Recombinational DNA Repair
PubMed: 29603285
DOI: 10.1002/bies.201700229