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DNA Repair Sep 2020Canonical DNA mismatch repair (MMR) excises base-base mismatches to increase the fidelity of DNA replication. Thus, loss of MMR leads to increased spontaneous... (Review)
Review
Canonical DNA mismatch repair (MMR) excises base-base mismatches to increase the fidelity of DNA replication. Thus, loss of MMR leads to increased spontaneous mutagenesis. MMR genes also are involved in the suppression of mutagenic, and the induction of protective, responses to various types of DNA damage. In this review we describe these non-canonical roles of MMR at different lesion types. Loss of non-canonical MMR gene functions may have important ramifications for the prevention, development and treatment of colorectal cancer associated with inherited MMR gene defects in Lynch syndrome. This graphical review pays tribute to Samuel H. Wilson. Sam not only made seminal contributions to understanding base excision repair, particularly with respect to structure-function relationships in DNA polymerase β but also, as Editor of DNA Repair, has maintained a high standard of the journal.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA; DNA Damage; DNA Mismatch Repair; DNA Replication; Humans; Mutagenesis
PubMed: 33087264
DOI: 10.1016/j.dnarep.2020.102923 -
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 -
Journal of Molecular Biology Oct 2018DNA mismatch repair (MMR) is a DNA excision-resynthesis process that principally enhances replication fidelity. Highly conserved MutS (MSH) and MutL (MLH/PMS) homologs... (Review)
Review
DNA mismatch repair (MMR) is a DNA excision-resynthesis process that principally enhances replication fidelity. Highly conserved MutS (MSH) and MutL (MLH/PMS) homologs initiate MMR and in higher eukaryotes act as DNA damage sensors that can trigger apoptosis. MSH proteins recognize mismatched nucleotides, whereas the MLH/PMS proteins mediate multiple interactions associated with downstream MMR events including strand discrimination and strand-specific excision that are initiated at a significant distance from the mismatch. Remarkably, the biophysical functions of the MLH/PMS proteins have been elusive for decades. Here we consider recent observations that have helped to define the mechanics of MLH/PMS proteins and their role in choreographing MMR. We highlight the stochastic nature of DNA interactions that have been visualized by single-molecule analysis and the plasticity of protein complexes that employ thermal diffusion to complete the progressions of MMR.
Topics: Animals; DNA; DNA Mismatch Repair; Humans; Kinetics; MutL Proteins; Signal Transduction; Single Molecule Imaging; Stochastic Processes
PubMed: 29864444
DOI: 10.1016/j.jmb.2018.05.039 -
Revista de Gastroenterologia de Mexico... 2022A frequent task in the study of colorectal carcinomas (CRC) is to identify tumors harboring deficient DNA mismatch repair systems (dMMR), which are associated with...
INTRODUCTION AND AIMS
A frequent task in the study of colorectal carcinomas (CRC) is to identify tumors harboring deficient DNA mismatch repair systems (dMMR), which are associated with microsatellite instability. Given that there is scant information on those tumors in Mexican patients, our aim was to describe their frequency, clinical and pathologic characteristics, and results, which are necessary for future trials.
MATERIALS AND METHODS
A consecutive series of CRC patients, treated and followed at a tertiary care center was performed. The clinical and pathologic variables and the risk of hereditary or familial cancer syndrome were retrieved. The original slides and hMLH1, hPMS2, hMSH2, hMSH6 immunohistochemistry were evaluated. Tumors with an absence of at least one protein were considered dMMR. Differences were contrasted, utilizing non-parametric tests.
RESULTS
One hundred and forty-four patients were included, with a median age of 65 years. A total of 134/93% patients presented with sporadic CRC, 8/5.6% had a family history of CRC, and 2/1.4% met the diagnostic criteria for hereditary non-polyposis colon cancer, according to the Amsterdam and Bethesda criteria. dMMR tumors were found in 39 patients, distributed among the three groups. They were locally advanced (p<0.001), right-sided, had the mucinous phenotype, and harbored a Crohn's-like lymphoid reaction (all three features, p<0.04). Adjuvant or palliative chemotherapy was administered to 57 (39.6%), concomitant chemoradiotherapy to 24 (16.7%), but 63 (43.8%) patients received no additional treatment to surgery. Five-year follow-up was completed in 131 of the patients and the outcomes alive-with-disease or died-of-disease were more frequently observed in the proficient (pMMR) lesions.
CONCLUSIONS
In the present pre-FOLFOX case series, outcomes were better in dMMR CRC than in proficient lesions.
Topics: Humans; DNA Mismatch Repair; Follow-Up Studies; Colorectal Neoplasms; Microsatellite Instability; Phenotype
PubMed: 35661637
DOI: 10.1016/j.rgmxen.2022.05.017 -
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 -
Modern Pathology : An Official Journal... Mar 2024Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch...
Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.
Topics: Female; Humans; DNA Mismatch Repair; MutL Protein Homolog 1; Endometrial Neoplasms; Germ-Line Mutation; Mismatch Repair Endonuclease PMS2; Microsatellite Instability; DNA Methylation
PubMed: 38191122
DOI: 10.1016/j.modpat.2024.100423 -
Taiwanese Journal of Obstetrics &... Sep 2022
Topics: DNA; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans
PubMed: 36088038
DOI: 10.1016/j.tjog.2022.05.012 -
DNA Repair Sep 2020DNA mismatch repair (MMR) maintains genomic stability primarily by correcting replication errors. Defects in MMR lead to cancers and cause resistance to many... (Review)
Review
DNA mismatch repair (MMR) maintains genomic stability primarily by correcting replication errors. Defects in MMR lead to cancers and cause resistance to many chemotherapeutic drugs. Emerging evidence reveals that MMR is coupled with replication and precisely regulated in the context of chromatin; strikingly, tumors defective in MMR are highly responsive to immune checkpoint blockade therapy. As a tribute to Dr. Samuel Wilson for his many scientific contributions to the field of DNA repair and his leadership as Editor-in-Chief of the journal DNA Repair, we summarize recent developments in research on MMR at the chromatin level, its implications for tumorigenesis, and its therapeutic potential.
Topics: Carcinogenesis; Chromatin; DNA Damage; DNA Mismatch Repair; Humans; Neoplasms
PubMed: 33087261
DOI: 10.1016/j.dnarep.2020.102918 -
Clinica Chimica Acta; International... Apr 2023Drugs targeting DNA repair have developed rapidly in cancer therapy, and numerous inhibitors have already been utilized in preclinical and clinical stages. To optimize... (Review)
Review
Drugs targeting DNA repair have developed rapidly in cancer therapy, and numerous inhibitors have already been utilized in preclinical and clinical stages. To optimize the selection of patients for treatment, it is essential to discover biomarkers to anticipate chemotherapy response. The DNA mismatch repair (MMR) pathway is closely correlated with cancer susceptibility and plays an important role in the occurrence and development of cancers. Here, we give a concise introduction of the MMR genes and focus on the potential biomarkers of chemotherapeutic response and resistance. It has been clarified that the status of MMR may affect the outcome of chemotherapy. However, the specific underlying mechanisms as well as contradictory results continue to raise considerable controversy and concern. In this review, we summarize the current literature to provide a general overview.
Topics: Humans; DNA Mismatch Repair; DNA Repair; Neoplasms; Biomarkers; Drug Resistance, Neoplasm
PubMed: 37060988
DOI: 10.1016/j.cca.2023.117338 -
Cancer Science Jun 2024Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing... (Review)
Review
Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.
Topics: Humans; Microsatellite Instability; Neoplasms; High-Throughput Nucleotide Sequencing; DNA Mismatch Repair; Colorectal Neoplasms; Immune Checkpoint Inhibitors; Biomarkers, Tumor; Immunotherapy; Mutation
PubMed: 38528657
DOI: 10.1111/cas.16160