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Neurosurgery Clinics of North America Apr 2021Mismatch repair (MMR) is a highly conserved DNA repair pathway that is critical for the maintenance of genomic integrity. This pathway targets base substitution and... (Review)
Review
Mismatch repair (MMR) is a highly conserved DNA repair pathway that is critical for the maintenance of genomic integrity. This pathway targets base substitution and insertion-deletion mismatches, which primarily arise from replication errors that escape DNA polymerase proof-reading function. Here, the authors review key concepts in the molecular mechanisms of MMR in response to alkylation damage, approaches to detect MMR status in the clinic, and the clinical relevance of this pathway in glioblastoma multiforme treatment response and resistance.
Topics: Antineoplastic Agents, Alkylating; DNA Mismatch Repair; Glioblastoma; Humans; Temozolomide
PubMed: 33781500
DOI: 10.1016/j.nec.2020.12.009 -
Current Opinion in Urology Nov 2010To highlight the significance of the abnormal DNA repair mechanism in male infertility. (Review)
Review
PURPOSE OF REVIEW
To highlight the significance of the abnormal DNA repair mechanism in male infertility.
RECENT FINDINGS
DNA repair defects cause a variety of spermatogenic defects in mouse models. Evidence is accumulating to demonstrate the importance of DNA repair defects in human nonobstructive azoospermia. Epigenetic changes may also play a crucial role in infertility.
SUMMARY
The DNA in the cell needs to be constantly repaired to ensure fidelity of DNA replication, to maintain genome stability and to ensure propagation of species. The DNA repair and recombination machineries are highly conserved across the species and inactivation of these pathways may lead to replication and recombination errors. This review summarizes the different types of DNA lesions and DNA repair pathways, particularly focusing on highly conserved meiotic regulators, the DNA mismatch repair proteins. Targeted deletions of some of these proteins result in infertility and predisposes to tumor in mutant mouse models. There is evidence for loss of some of these proteins in human male infertility. Because defective DNA repair is associated with a mutator phenotype, the risk of transmission to the offspring of these otherwise infertile men conceived using an assisted reproductive technology needs further evaluation.
Topics: Animals; DNA Mismatch Repair; DNA Replication; Epigenesis, Genetic; Humans; Infertility, Male; Male; Mice; Models, Animal
PubMed: 20852424
DOI: 10.1097/MOU.0b013e32833f1c21 -
Pathology Oncology Research : POR 2024Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers... (Review)
Review
Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.
Topics: Humans; Microsatellite Instability; DNA Mismatch Repair; Biomarkers, Tumor; Neoplasms; Prognosis
PubMed: 38655493
DOI: 10.3389/pore.2024.1611719 -
Gastrointestinal Endoscopy Clinics of... Jan 2022Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes,... (Review)
Review
Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, or deletions in EPCAM. LS leads to an increased risk of intestinal and extraintestinal cancers, of which colorectal and endometrial cancers are the most common. Individuals at risk for LS can be identified by using clinical criteria, prediction models, and universal tumor testing. Understanding each of these tools, including limitations and mimics of LS, is essential to the early identification of at-risk individuals.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; MutL Protein Homolog 1
PubMed: 34798986
DOI: 10.1016/j.giec.2021.09.002 -
Sao Paulo Medical Journal = Revista... Jan 2009Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in... (Review)
Review
Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50%) and MSH2 (40%), while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Germ-Line Mutation; Humans
PubMed: 19466295
DOI: 10.1590/s1516-31802009000100010 -
DNA Repair Feb 2016The principal DNA mismatch repair proteins MutS and MutL are versatile enzymes that couple DNA mismatch or damage recognition to other cellular processes. Besides... (Review)
Review
The principal DNA mismatch repair proteins MutS and MutL are versatile enzymes that couple DNA mismatch or damage recognition to other cellular processes. Besides interaction with their DNA substrates this involves transient interactions with other proteins which is triggered by the DNA mismatch or damage and controlled by conformational changes. Both MutS and MutL proteins have ATPase activity, which adds another level to control their activity and interactions with DNA substrates and other proteins. Here we focus on the protein-protein interactions, protein interaction sites and the different levels of structural knowledge about the protein complexes formed with MutS and MutL during the mismatch repair reaction.
Topics: Animals; DNA Mismatch Repair; Humans; Models, Biological; Multiprotein Complexes; Protein Binding; Protein Interaction Mapping; Protein Multimerization
PubMed: 26725162
DOI: 10.1016/j.dnarep.2015.11.013 -
Pathologie (Heidelberg, Germany) Sep 2023Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for... (Review)
Review
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Multicenter Studies as Topic
PubMed: 37548948
DOI: 10.1007/s00292-023-01209-1 -
DNA Repair Feb 2016At the heart of the mismatch repair (MMR) system are proteins that recognize mismatches in DNA. Such mismatches can be mispairs involving normal or damaged bases or... (Review)
Review
At the heart of the mismatch repair (MMR) system are proteins that recognize mismatches in DNA. Such mismatches can be mispairs involving normal or damaged bases or insertion/deletion loops due to strand misalignment. When such mispairs are generated during replication or recombination, MMR will direct removal of an incorrectly paired base or block recombination between nonidentical sequences. However, when mispairs are recognized outside the context of replication, proper strand discrimination between old and new DNA is lost, and MMR can act randomly and mutagenically on mispaired DNA. Such non-canonical actions of MMR are important in somatic hypermutation and class switch recombination, expansion of triplet repeats, and potentially in mutations arising in nondividing cells. MMR involvement in damage recognition and signaling is complex, with the end result likely dependent on the amount of DNA damage in a cell.
Topics: Animals; Base Sequence; DNA Mismatch Repair; DNA Replication; Gene Conversion; Humans; Models, Biological; Molecular Sequence Data; Mutagenesis
PubMed: 26698648
DOI: 10.1016/j.dnarep.2015.11.020 -
Journal of Molecular Biology Oct 2018DNA mismatch repair (MMR) corrects DNA base-pairing errors that occur during DNA replication. MMR catalyzes strand-specific DNA degradation and resynthesis by dynamic... (Review)
Review
DNA mismatch repair (MMR) corrects DNA base-pairing errors that occur during DNA replication. MMR catalyzes strand-specific DNA degradation and resynthesis by dynamic molecular coordination of sequential downstream pathways. The temporal and mechanistic order of molecular events is essential to insure interactions in MMR that occur over long distances on the DNA. Biophysical real-time studies of highly conserved components on mismatched DNA have shed light on the mechanics of MMR. Single-molecule imaging has visualized stochastically coordinated MMR interactions that are based on thermal fluctuation-driven motions. In this review, we describe the role of diffusivity and stochasticity in MMR beginning with mismatch recognition through strand-specific excision. We conclude with a perspective of the possible research directions that should solve the remaining questions in MMR.
Topics: Animals; Biophysical Phenomena; DNA; DNA Mismatch Repair; Diffusion; Humans; Multiprotein Complexes; Stochastic Processes; Thermodynamics
PubMed: 29792877
DOI: 10.1016/j.jmb.2018.05.032 -
DNA Repair Feb 2016
Topics: Biophysical Phenomena; DNA Mismatch Repair; Disease; Humans; Microsatellite Instability; Translational Research, Biomedical
PubMed: 26777339
DOI: 10.1016/j.dnarep.2015.11.007