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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 -
DNA Repair Feb 2016DNA mismatch repair influences the outcome of recombination events between diverging DNA sequences. Here we discuss how mismatch repair proteins are active in different... (Review)
Review
DNA mismatch repair influences the outcome of recombination events between diverging DNA sequences. Here we discuss how mismatch repair proteins are active in different homologous recombination subpathways and specific reaction steps, resulting in differential modulation of these recombination events, with a focus on the mechanism of heteroduplex rejection during the inhibition of recombination between slightly diverged (homeologous) DNA sequences.
Topics: Animals; DNA Mismatch Repair; DNA Replication; Homologous Recombination; Humans; Models, Biological; Nucleic Acid Heteroduplexes
PubMed: 26739221
DOI: 10.1016/j.dnarep.2015.11.010 -
DNA Repair Sep 2021DNA mismatch repair (MMR) corrects non-Watson-Crick basepairs generated by replication errors, recombination intermediates, and some forms of chemical damage to DNA. In... (Review)
Review
DNA mismatch repair (MMR) corrects non-Watson-Crick basepairs generated by replication errors, recombination intermediates, and some forms of chemical damage to DNA. In MutS and MutL homolog-dependent MMR, damaged bases do not identify the error-containing daughter strand that must be excised and resynthesized. In organisms like Escherichia coli that use methyl-directed MMR, transient undermethylation identifies the daughter strand. For other organisms, growing in vitro and in vivo evidence suggest that strand discrimination is mediated by DNA replication-associated daughter strand nicks that direct asymmetric loading of the replicative clamp (the β-clamp in bacteria and the proliferating cell nuclear antigen, PCNA, in eukaryotes). Structural modeling suggests that replicative clamps mediate strand specificity either through the ability of MutL homologs to recognize the fixed orientation of the daughter strand relative to one face of the replicative clamps or through parental strand-specific diffusion of replicative clamps on DNA, which places the daughter strand in the MutL homolog endonuclease active site. Finally, identification of bacteria that appear to lack strand discrimination mediated by a replicative clamp and a pre-existing nick suggest that other strand discrimination mechanisms exist or that these organisms perform MMR by generating a double-stranded DNA break intermediate, which may be analogous to NucS-mediated MMR.
Topics: Bacteria; DNA; DNA Mismatch Repair; DNA Replication; Eukaryota; Humans
PubMed: 34171627
DOI: 10.1016/j.dnarep.2021.103161 -
Modern Pathology : An Official Journal... Nov 2022In managing patients with solid tumors, the value of detecting the status of tumor DNA mismatch repair function is widely recognized. Mismatch repair protein... (Review)
Review
In managing patients with solid tumors, the value of detecting the status of tumor DNA mismatch repair function is widely recognized. Mismatch repair protein immunohistochemistry and molecular microsatellite instability testing constitute the two major test modalities currently in use, yet each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein immunohistochemistry abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. The current criteria and cutoff values for defining microsatellite instability-high are developed primarily according to colorectal tumors. Non-colorectal cases, and occasionally even colorectal tumors, that are mismatch repair-deficient by immunohistochemistry but not microsatellite instability-high by current standards are being recognized. Emerging data suggest that these immunohistochemistry abnormal / non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. Whether these tumors respond to immunotherapy is a question still to be addressed. It is imperative that pathologists as well as clinicians and investigators be aware of such intricacies regarding routine immunohistochemistry and microsatellite instability testing and the results they generate. This review summarizes our current understanding of the advantages and limitations of these tests and offer our view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the test results.
Topics: Humans; Immunohistochemistry; Microsatellite Instability; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 35668150
DOI: 10.1038/s41379-022-01109-4 -
Journal of Huntington's Disease 2021DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the... (Review)
Review
DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of DNA damage. Counterintuitively, MMR is also involved in the generation of mutations, as evidenced by its role in causing somatic triplet repeat expansion in Huntington's disease (HD) and other neurodegenerative disorders. In this review, we discuss the current state of mechanistic knowledge of MMR and review the roles of key enzymes in this pathway. We also present the evidence for mutagenic function of MMR in CAG repeat expansion and consider mechanistic hypotheses that have been proposed. Understanding the role of MMR in CAG expansion may shed light on potential avenues for therapeutic intervention in HD.
Topics: DNA Mismatch Repair; Humans; Huntington Disease; Trinucleotide Repeat Expansion
PubMed: 33579865
DOI: 10.3233/JHD-200438 -
Genes & Development Oct 2023The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do...
The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8 T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.
Topics: Animals; Mice; DNA Mismatch Repair; CD8-Positive T-Lymphocytes; Synthetic Lethal Mutations; DNA; Immunotherapy
PubMed: 37932012
DOI: 10.1101/gad.351084.123 -
Cells Jun 2021Mismatch Repair (MMR) is an important and conserved keeper of the maintenance of genetic information. Miroslav Radman's contributions to the field of MMR are multiple... (Review)
Review
Mismatch Repair (MMR) is an important and conserved keeper of the maintenance of genetic information. Miroslav Radman's contributions to the field of MMR are multiple and tremendous. One of the most notable was to provide, along with Bob Wagner and Matthew Meselson, the first direct evidence for the existence of the methyl-directed MMR. The purpose of this review is to outline several aspects and biological implications of MMR that his work has helped unveil, including the role of MMR during replication and recombination editing, and the current understanding of its mechanism. The review also summarizes recent discoveries related to the visualization of MMR components and discusses how it has helped shape our understanding of the coupling of mismatch recognition to replication. Finally, the author explains how visualization of MMR components has paved the way to the study of spontaneous mutations in living cells in real time.
Topics: Animals; DNA Damage; DNA Mismatch Repair; DNA Replication; Genomic Instability; Humans; Mutation
PubMed: 34207040
DOI: 10.3390/cells10061535 -
BioMed Research International 2017Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in... (Review)
Review
Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation.
Topics: Biomarkers, Tumor; Clinical Trials as Topic; DNA Mismatch Repair; Humans; Immunotherapy; Inflammation; Microsatellite Instability; Mutation; Neoplasms
PubMed: 28770222
DOI: 10.1155/2017/4719194 -
Journal of Clinical Oncology : Official... Jan 2020
Topics: Arm; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Nivolumab
PubMed: 31794325
DOI: 10.1200/JCO.19.02860 -
DNA Repair Dec 2018DNA mismatch repair (MMR) is a highly conserved process and ensures the removal of mispaired DNA bases and insertion-deletion loops right after replication. For this, a... (Review)
Review
DNA mismatch repair (MMR) is a highly conserved process and ensures the removal of mispaired DNA bases and insertion-deletion loops right after replication. For this, a MutSα or MutSβ protein complex recognizes the DNA damage, MutLα nicks the erroneous strand, exonuclease 1 removes the wrong nucleotides, DNA polymerase δ refills the gap and DNA ligase I joins the fragments to seal the nicks and complete the repair process. The failure to accomplish these functions is associated with higher mutation rates and may lead to cancer, which highlights the importance of MMR by the maintenance of genomic stability. The post-replicative MMR implies that involved proteins are regulated at several levels, including posttranslational modifications (PTMs). Phosphorylation is one of the most common and major PTMs. Suitable with its regulatory force phosphorylation was shown to influence MMR factors thereby adjusting eukaryotic MMR activity. In this review, we summarized the current knowledge of the role of phosphorylation of MMR process involved proteins and their functional relevance.
Topics: Animals; Cell Cycle; DNA Mismatch Repair; Humans; Phosphorylation; Proteolysis
PubMed: 30249411
DOI: 10.1016/j.dnarep.2018.09.001