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Angewandte Chemie (International Ed. in... Jul 2016DNA molecules are not completely stable, they are subject to chemical or photochemical damage and errors that occur during DNA replication resulting in mismatched base... (Review)
Review
DNA molecules are not completely stable, they are subject to chemical or photochemical damage and errors that occur during DNA replication resulting in mismatched base pairs. Through mechanistic studies Paul Modrich showed how replication errors are corrected by strand-directed mismatch repair in Escherichia coli and human cells.
Topics: DNA; DNA Helicases; DNA Methylation; DNA Mismatch Repair; Escherichia coli; Escherichia coli Proteins; Humans; MutL Protein Homolog 1; MutL Proteins; MutS DNA Mismatch-Binding Protein
PubMed: 27198632
DOI: 10.1002/anie.201601412 -
DNA Repair Feb 2016Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer... (Review)
Review
Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies.
Topics: Animals; Biomedical Research; DNA Mismatch Repair; Disease Models, Animal; Genes, Tumor Suppressor; Humans; Mice; Mutation; Neoplasms
PubMed: 26708047
DOI: 10.1016/j.dnarep.2015.11.015 -
DNA Repair Sep 2020Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA... (Review)
Review
Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA replication, repair, recombination, and gene transcription. Emerging evidence indicates that DNA base damage and base excision repair (BER) play an active role in regulating somatic TNR instability. These processes may potentially modulate the onset and progression of TNR-related diseases, given that TNRs are hotspots of DNA base damage that are present in mammalian cells with a high frequency. In this review, we discuss the recent advances in our understanding of the molecular mechanisms underlying BER-mediated TNR instability. We initially discuss the roles of the BER pathway and locations of DNA base lesions in TNRs and their interplay with non-B form DNA structures in governing repeat instability. We then discuss how the coordinated activities of BER enzymes can modulate a balance between the removal and addition of TNRs to regulate somatic TNR instability. We further discuss how this balance can be disrupted by the crosstalk between BER and DNA mismatch repair (MMR) machinery resulting in TNR expansion. Finally, we suggest future directions regarding BER-mediated somatic TNR instability and its association with TNR disease prevention and treatment.
Topics: Animals; DNA; DNA Damage; DNA Mismatch Repair; DNA Repair; Humans; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 33087278
DOI: 10.1016/j.dnarep.2020.102912 -
DNA Repair Nov 2018DNA mismatch repair (MMR) is an evolutionally conserved genome maintenance pathway and is well known for its role in maintaining replication fidelity by correcting... (Review)
Review
DNA mismatch repair (MMR) is an evolutionally conserved genome maintenance pathway and is well known for its role in maintaining replication fidelity by correcting biosynthetic errors generated during DNA replication. However, recent studies have shown that MMR preferentially protects actively transcribed genes from mutation during both DNA replication and transcription. This review describes the recent discoveries in this area. Potential mechanisms by which MMR safeguards actively transcribed genes are also discussed.
Topics: DNA; DNA Mismatch Repair; DNA-Binding Proteins; Eukaryota; Humans; Mutation; Transcription, Genetic
PubMed: 30174300
DOI: 10.1016/j.dnarep.2018.08.010 -
Journal of Gastrointestinal Cancer Sep 2023Mismatch repair immunohistochemistry (MMR IHC) or microsatellite instability (MSI) testing is now routinely performed in patients with colorectal cancer (CRC) to select... (Review)
Review
INTRODUCTION
Mismatch repair immunohistochemistry (MMR IHC) or microsatellite instability (MSI) testing is now routinely performed in patients with colorectal cancer (CRC) to select those requiring Lynch syndrome testing. MMR IHC is also carried out on CRC and upper gastrointestinal (GI) cancers to select patients for immunotherapy. We review the Royal Marsden Hospital's pathway of molecular to germline testing for Lynch syndrome in the context of NICE guidance and the National Test Directory.
METHODS
We conducted (i) a retrospective audit of adherence to NICE guidance DG27 for patients diagnosed with CRC March 2017-August 2018 and (ii) a retrospective service evaluation of MMR IHC/Lynch syndrome testing in patients diagnosed with upper GI cancers January 2019-2020.
RESULTS
Of 394 patients with CRC, 346 (87.8%) had MMR IHC testing. Thirty-eight of 346 (10.9%) were MMR deficient (MMR-D) and 5 (1.4%) were found to have pathogenic germline variants causing Lynch syndrome. Of 405 patients with upper GI cancers, 221 (54.6%) had MMR IHC testing. Ten of 221 (4.5%) were MMR-D and 1 (0.5%) had a pathogenic germline variant causing Lynch syndrome.
DISCUSSION
This study highlights the small but significant number of patients, with CRC or upper GI cancers, which were caused by Lynch syndrome. It also highlights weaknesses in our testing pathway that limit access to germline testing. As MMR testing increases, it is important that clinicians are aware that patients with MMR-D tumours require reflex somatic testing or referral for germline testing. We have incorporated the guidelines into a pathway for use in clinics and multidisciplinary teams.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Retrospective Studies; Early Detection of Cancer; Gastrointestinal Neoplasms; Microsatellite Instability; Immunotherapy
PubMed: 36018445
DOI: 10.1007/s12029-022-00859-3 -
International Journal of Cancer Nov 2022Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative... (Meta-Analysis)
Meta-Analysis
Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta-analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8-65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high-quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.
Topics: Brain Neoplasms; Carcinoma, Ovarian Epithelial; Colorectal Neoplasms; DNA Mismatch Repair; Female; Humans; Microsatellite Instability; Neoplastic Syndromes, Hereditary; Ovarian Neoplasms; Prevalence; Prospective Studies
PubMed: 35792468
DOI: 10.1002/ijc.34165 -
Digestive Diseases (Basel, Switzerland) 2023The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA... (Review)
Review
BACKGROUND
The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy.
SUMMARY
In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays.
KEY MESSAGES
The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.
Topics: Humans; Microsatellite Instability; DNA Mismatch Repair; Colorectal Neoplasms; Adenocarcinoma
PubMed: 37231848
DOI: 10.1159/000531003 -
Nucleic Acids Research Feb 2023The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair...
The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.
Topics: Animals; Mice; DNA; DNA Mismatch Repair; DNA Repair; Mutation; MutS Homolog 2 Protein
PubMed: 36715327
DOI: 10.1093/nar/gkad015 -
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 Aug 2014Base-pair mismatches that occur during DNA replication or recombination can reduce genetic stability or conversely increase genetic diversity. The genetics and... (Review)
Review
Base-pair mismatches that occur during DNA replication or recombination can reduce genetic stability or conversely increase genetic diversity. The genetics and biophysical mechanism of mismatch repair (MMR) has been extensively studied since its discovery nearly 50 years ago. MMR is a strand-specific excision-resynthesis reaction that is initiated by MutS homolog (MSH) binding to the mismatched nucleotides. The MSH mismatch-binding signal is then transmitted to the immediate downstream MutL homolog (MLH/PMS) MMR components and ultimately to a distant strand scission site where excision begins. The mechanism of signal transmission has been controversial for decades. We have utilized single molecule Forster Resonance Energy Transfer (smFRET), Fluorescence Tracking (smFT) and Polarization Total Internal Reflection Fluorescence (smP-TIRF) to examine the interactions and dynamic behaviors of single Thermus aquaticus MutS (TaqMutS) particles on mismatched DNA. We determined that TaqMutS forms an incipient clamp to search for a mismatch in ~1 s intervals by 1-dimensional (1D) thermal fluctuation-driven rotational diffusion while in continuous contact with the helical duplex DNA. When MutS encounters a mismatch it lingers for ~3 s to exchange bound ADP for ATP (ADP→ATP exchange). ATP binding by TaqMutS induces an extremely stable clamp conformation (~10 min) that slides off the mismatch and moves along the adjacent duplex DNA driven simply by 1D thermal diffusion. The ATP-bound sliding clamps rotate freely while in discontinuous contact with the DNA. The visualization of a train of MSH proteins suggests that dissociation of ATP-bound sliding clamps from the mismatch permits multiple mismatch-dependent loading events. These direct observations have provided critical clues into understanding the molecular mechanism of MSH proteins during MMR.
Topics: Animals; DNA Mismatch Repair; Fluorescence Resonance Energy Transfer; Humans; Microscopy, Fluorescence; MutS DNA Mismatch-Binding Protein
PubMed: 24629484
DOI: 10.1016/j.dnarep.2014.02.014