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DNA Repair Aug 2014DNA mismatch repair, which involves is a widely conserved set of proteins, is essential to limit genetic drift in all organisms. The same system of proteins plays key... (Review)
Review
DNA mismatch repair, which involves is a widely conserved set of proteins, is essential to limit genetic drift in all organisms. The same system of proteins plays key roles in many cancer related cellular transactions in humans. Although the basic process has been reconstituted in vitro using purified components, many fundamental aspects of DNA mismatch repair remain hidden due in part to the complexity and transient nature of the interactions between the mismatch repair proteins and DNA substrates. Single molecule methods offer the capability to uncover these transient but complex interactions and allow novel insights into mechanisms that underlie DNA mismatch repair. In this review, we discuss applications of single molecule methodology including electron microscopy, atomic force microscopy, particle tracking, FRET, and optical trapping to studies of DNA mismatch repair. These studies have led to formulation of mechanistic models of how proteins identify single base mismatches in the vast background of matched DNA and signal for their repair.
Topics: Amino Acid Sequence; Animals; DNA Mismatch Repair; DNA Repair Enzymes; Fluorescence Resonance Energy Transfer; Humans; Microscopy, Atomic Force; Molecular Sequence Data; Optical Tweezers
PubMed: 24746644
DOI: 10.1016/j.dnarep.2014.03.007 -
Expert Reviews in Molecular Medicine Sep 2022Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions... (Review)
Review
Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions (increases) or contractions (decreases) in the number of repeat units. Some microsatellite instability (MSI) is seen at multiple STRs within a single cell and is associated with certain types of cancer. A second form of MSI is characterised by expansion of a single gene-specific STR and such expansions are responsible for a group of 40+ human genetic disorders known as the repeat expansion diseases (REDs). While the mismatch repair (MMR) pathway prevents genome-wide MSI, emerging evidence suggests that some MMR factors are directly involved in generating expansions in the REDs. Thus, MMR suppresses some forms of expansion while some MMR factors promote expansion in other contexts. This review will cover what is known about the paradoxical effect of MMR on microsatellite expansion in mammalian cells.
Topics: Animals; DNA Mismatch Repair; Genomic Instability; Humans; Mammals; Microsatellite Instability; Microsatellite Repeats
PubMed: 36059110
DOI: 10.1017/erm.2022.16 -
DNA Repair Feb 2016MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these... (Review)
Review
MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these functions, DNA mismatch repair is the major one. The loss of MutLα abolishes DNA mismatch repair, thereby predisposing humans to cancer. MutLα has an endonuclease activity that is required for DNA mismatch repair. The endonuclease activity of MutLα depends on the DQHA(X)2E(X)4E motif which is a part of the active site of the nuclease. This motif is also present in many bacterial MutL and eukaryotic MutLγ proteins, DNA mismatch repair system factors that are homologous to MutLα. Recent studies have shown that yeast MutLγ and several MutL proteins containing the DQHA(X)2E(X)4E motif possess endonuclease activities. Here, we review the endonuclease activities of MutLα and its homologs in the context of DNA mismatch repair.
Topics: Animals; DNA Mismatch Repair; DNA Repair Enzymes; Endonucleases; Humans; Models, Biological; Sequence Homology, Amino Acid
PubMed: 26719141
DOI: 10.1016/j.dnarep.2015.11.023 -
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 -
Frontiers in Immunology 2022Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized... (Review)
Review
Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized to repair DNA damages during different stages of the cell cycle, comprehending base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ). The unprecedented benefits achieved with immunological checkpoint inhibitors (ICIs) in tumors with mismatch repair deficiency (dMMR) have prompted efforts to extend this efficacy to tumors with HR deficiency (HRD), which are greatly sensitive to chemotherapy or PARP inhibitors, and also considered highly immunogenic. However, an in-depth understanding of HRD's molecular underpinnings has pointed to essential singularities that might impact ICIs sensitivity. Here we address the main molecular aspects of HRD that underlie a differential profile of efficacy and resistance to the treatment with ICIs compared to other DDR deficiencies.
Topics: Cell Cycle; DNA Damage; DNA End-Joining Repair; DNA Mismatch Repair; DNA Repair; Homologous Recombination; Humans; Immune Checkpoint Inhibitors; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 35211121
DOI: 10.3389/fimmu.2022.826577 -
Expert Review of Clinical Pharmacology Aug 2017Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair... (Review)
Review
Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20-25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer in the coming years. Work is needed to define the optimal tissue to test, and to define the natural history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with 'actionable' mutations are now needed.
Topics: Antineoplastic Agents; DNA Mismatch Repair; DNA Repair; Drugs, Investigational; Genomics; Humans; Immunotherapy; Male; Microsatellite Instability; Molecular Targeted Therapy; Mutation; Prognosis; Prostatic Neoplasms, Castration-Resistant
PubMed: 28573914
DOI: 10.1080/17512433.2017.1338138 -
Annals of Surgical Oncology Dec 2023Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite... (Review)
Review
Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite instability (MSI) has become a major molecular typing approach for gastric cancer. MSI is well recognized for its important role during the immunotherapy of advanced GC. However, its value remains unclear in resectable gastric cancer. The reported incidence of microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) in resectable gastric cancer varies widely, with no consensus reached on the value of postoperative adjuvant therapy in patients with MSI-H/dMMR resectable GC. It has been established that MSI-H/dMMR tumor cells can elicit an endogenous immune antitumor response and ubiquitously express immune checkpoint ligands such as PD-1 or PD-L1. On the basis of these considerations, MSI-H/dMMR resectable GCs are responsive to adjuvant immunotherapy, although limited research has hitherto been conducted. In this review, we comprehensively describe the differences in geographic distribution and pathological stages in patients with MSI-H/dMMR with resectable gastric cancer and explore the value of adjuvant chemotherapy and immunotherapy on MSI-H/dMMR to provide a foothold for the individualized treatment of this patient population.
Topics: Humans; Stomach Neoplasms; DNA Mismatch Repair; Microsatellite Instability; Immunotherapy; Adjuvants, Immunologic; Colorectal Neoplasms
PubMed: 37667098
DOI: 10.1245/s10434-023-14103-0 -
Journal of Zhejiang University.... Jan 2016DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and... (Review)
Review
DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.
Topics: DNA; DNA Damage; DNA Mismatch Repair; Fertility; Genetic Markers; Genetic Predisposition to Disease; Humans; Infertility; Models, Genetic
PubMed: 26739522
DOI: 10.1631/jzus.B1500162 -
Journal of Medical Genetics Jul 2022Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR)...
BACKGROUND
Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including , , and play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation-caused cancer. In the current study, we addressed the issue by using the Chinese population as a model.
METHODS
We performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population.
RESULTS
We identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral.
CONCLUSION
Our study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.
Topics: China; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Germ-Line Mutation; Humans; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Prevalence
PubMed: 34172528
DOI: 10.1136/jmedgenet-2021-107886 -
Aging Aug 2017
Topics: Antibodies, Monoclonal, Humanized; BRCA2 Protein; Colorectal Neoplasms; DNA Mismatch Repair; ErbB Receptors; Humans; Microsatellite Instability; Mutation; Receptor Protein-Tyrosine Kinases
PubMed: 28783711
DOI: 10.18632/aging.101275