-
DNA Repair Jun 2019An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss... (Review)
Review
An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss of MMR function and tumorigenesis. The latter is evident as inheritance of mutations within the major MMR genes give rise to the cancer predisposition condition, Lynch syndrome. Nonetheless, how MMR loss contributes to tumorigenesis is not completely understood. In addition to preventing the accumulation of mutations, MMR also directs cellular responses, such as cell cycle checkpoint or apoptosis activation, to different forms of DNA damage. Understanding this MMR-dependent DNA damage response may provide insight into the full tumor suppressing capabilities of the MMR pathway. Here, we delve into the proposed mechanisms for the MMR-dependent response to DNA damaging agents. We discuss how these pre-clinical findings extend to the clinical treatment of cancers, emphasizing MMR status as a crucial variable in selection of chemotherapeutic regimens. Also, we discuss how loss of the MMR-dependent damage response could promote tumorigenesis via the establishment of a survival advantage to endogenous levels of stress in MMR-deficient cells.
Topics: DNA Damage; DNA Mismatch Repair; DNA-Directed DNA Polymerase; Humans; Neoplasms
PubMed: 30959407
DOI: 10.1016/j.dnarep.2019.03.009 -
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 -
Clinical Colorectal Cancer Sep 2022Colon cancer needs better screening and treatment options. Its incidence in the young population is rising. Recent changes in guidelines recommend beginning screening... (Review)
Review
Colon cancer needs better screening and treatment options. Its incidence in the young population is rising. Recent changes in guidelines recommend beginning screening for colon cancer at the age of 45. Circulating tumor DNA presents an opportunity to select patients for administration of adjuvant chemotherapy. Immunotherapy is an option for patients with a deficiency in mismatch repair proteins. However, its efficacy outside of this group of patients remains a challenge. Targeted therapies such as BRAF inhibitors are an option for patients with poor prognosis, for whom cytotoxic chemotherapy is not as effective. This review presents the recently published evidence regarding screening and treating patients with colon cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; DNA Mismatch Repair; Humans; Neoplasm Staging; Prognosis
PubMed: 35729033
DOI: 10.1016/j.clcc.2022.05.006 -
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 -
Frontiers in Immunology 2023Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation.... (Review)
Review
Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Stomach Neoplasms; Treatment Outcome; Immunotherapy; Tumor Microenvironment
PubMed: 37492581
DOI: 10.3389/fimmu.2023.1210164 -
Cold Spring Harbor Perspectives in... Mar 2015Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for... (Review)
Review
Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans.
Topics: Animals; Biological Evolution; DNA Breaks, Double-Stranded; DNA Mismatch Repair; Homologous Recombination; Humans; Meiosis; Models, Biological; Species Specificity
PubMed: 25731766
DOI: 10.1101/cshperspect.a022657 -
International Journal of Biological... 2022DNA mismatch repair (MMR) is an important pathway which helps to maintain genomic stability. Mutations in DNA MMR genes are found to promote cancer initiation and foster... (Review)
Review
DNA mismatch repair (MMR) is an important pathway which helps to maintain genomic stability. Mutations in DNA MMR genes are found to promote cancer initiation and foster tumor progression. Deficiency or inactivation of MMR results in microsatellite instability (MSI) which triggers neoantigen generation and impairs tumor growth. Immunotherapies targeting MMR can increase the burden of neoantigens in tumor cells. While MSI has been regarded as an important predictor of sensitivity and drug resistance for immunotherapy-based strategies. Different approaches targeting genomic instability have been demonstrated to be promising in malignancies derived from different tissues. Underlying MMR deficiency-associated immunogenicity is important for improving the therapeutic efficacy of immunotherapies. In this review we provide an overview of the MMR systems, their role in tumorigenesis, drug resistance, prognostic significance and potential targets for therapeutic treatment in human cancers, especially in hematological malignancies.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immunotherapy; Microsatellite Instability; Mutation
PubMed: 35541922
DOI: 10.7150/ijbs.71714 -
Mutation Research. Reviews in Mutation... Jul 2017DNA mismatch repair (MMR) is an important DNA repair pathway that plays critical roles in DNA replication fidelity, mutation avoidance and genome stability, all of which... (Review)
Review
DNA mismatch repair (MMR) is an important DNA repair pathway that plays critical roles in DNA replication fidelity, mutation avoidance and genome stability, all of which contribute significantly to the viability of cells and organisms. MMR is widely-used as a diagnostic biomarker for human cancers in the clinic, and as a biomarker of cancer susceptibility in animal model systems. Prokaryotic MMR is well-characterized at the molecular and mechanistic level; however, MMR is considerably more complex in eukaryotic cells than in prokaryotic cells, and in recent years, it has become evident that MMR plays novel roles in eukaryotic cells, several of which are not yet well-defined or understood. Many MMR-deficient human cancer cells lack mutations in known human MMR genes, which strongly suggests that essential eukaryotic MMR components/cofactors remain unidentified and uncharacterized. Furthermore, the mechanism by which the eukaryotic MMR machinery discriminates between the parental (template) and the daughter (nascent) DNA strand is incompletely understood and how cells choose between the EXO1-dependent and the EXO1-independent subpathways of MMR is not known. This review summarizes recent literature on eukaryotic MMR, with emphasis on the diverse cellular roles of eukaryotic MMR proteins, the mechanism of strand discrimination and cross-talk/interactions between and co-regulation of MMR and other DNA repair pathways in eukaryotic cells. The main conclusion of the review is that MMR proteins contribute to genome stability through their ability to recognize and promote an appropriate cellular response to aberrant DNA structures, especially when they arise during DNA replication. Although the molecular mechanism of MMR in the eukaryotic cell is still not completely understood, increased used of single-molecule analyses in the future may yield new insight into these unsolved questions.
Topics: Animals; DNA Mismatch Repair; DNA Replication; Eukaryotic Cells; Genomic Instability; Humans; Mutation; Sequence Analysis, DNA
PubMed: 28927527
DOI: 10.1016/j.mrrev.2017.07.001 -
Annual Review of Genetics 2015Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation,... (Review)
Review
Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome.
Topics: DNA; DNA Damage; DNA Mismatch Repair; DNA Replication; Escherichia coli; Genomic Instability; Humans; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 26436461
DOI: 10.1146/annurev-genet-112414-054722 -
International Journal of Clinical... Sep 2019Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family,... (Review)
Review
Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSĪ±, MutSĪ², respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.
Topics: Brain Neoplasms; Child; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA-Binding Proteins; Endometrial Neoplasms; Epithelial Cell Adhesion Molecule; Female; Genetic Counseling; Genetic Testing; Humans; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Mutation
PubMed: 31273487
DOI: 10.1007/s10147-019-01494-y