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Journal of Zhejiang University.... Jan 2016DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and... (Review)
Review
DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.
Topics: DNA; DNA Damage; DNA Mismatch Repair; Fertility; Genetic Markers; Genetic Predisposition to Disease; Humans; Infertility; Models, Genetic
PubMed: 26739522
DOI: 10.1631/jzus.B1500162 -
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 -
Haematologica May 2010
Topics: Brain Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Hematologic Neoplasms; Humans; Neoplasms; Syndrome
PubMed: 20442441
DOI: 10.3324/haematol.2009.021626 -
Frontiers in Immunology 2022Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized... (Review)
Review
Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized to repair DNA damages during different stages of the cell cycle, comprehending base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ). The unprecedented benefits achieved with immunological checkpoint inhibitors (ICIs) in tumors with mismatch repair deficiency (dMMR) have prompted efforts to extend this efficacy to tumors with HR deficiency (HRD), which are greatly sensitive to chemotherapy or PARP inhibitors, and also considered highly immunogenic. However, an in-depth understanding of HRD's molecular underpinnings has pointed to essential singularities that might impact ICIs sensitivity. Here we address the main molecular aspects of HRD that underlie a differential profile of efficacy and resistance to the treatment with ICIs compared to other DDR deficiencies.
Topics: Cell Cycle; DNA Damage; DNA End-Joining Repair; DNA Mismatch Repair; DNA Repair; Homologous Recombination; Humans; Immune Checkpoint Inhibitors; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 35211121
DOI: 10.3389/fimmu.2022.826577 -
The Journal of Pathology. Clinical... Mar 2022Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary,...
Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary, and pancreatic carcinomas (DC, AC, and PC, respectively) is largely unknown. We explored the prevalence of dMMR and the underlying molecular mechanisms in a retrospectively collected cohort of 90 early-onset carcinomas of duodenal, ampullary, and pancreatic origin. dMMR was most prevalent in early-onset DCs (47.8%); more than half of those were associated with hereditary cancer syndromes (LS or constitutional mismatch repair deficiency syndrome). All dMMR AC and PC were due to LS. Concordance of dMMR with underlying hereditary condition warrants ubiquitous dMMR testing in all early-onset DC, AC, and PC.
Topics: Brain Neoplasms; Carcinoma; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Middle Aged; Neoplastic Syndromes, Hereditary; Retrospective Studies
PubMed: 34873870
DOI: 10.1002/cjp2.252 -
Cell Cycle (Georgetown, Tex.) Aug 2015
Topics: Animals; DNA Damage; DNA Mismatch Repair; Humans
PubMed: 26102362
DOI: 10.1080/15384101.2015.1063288 -
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 -
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 -
DNA Repair Jul 2014DNA mismatch repair (MMR) maintains genome stability primarily by repairing DNA replication-associated mispairs. Because loss of MMR function increases the mutation... (Review)
Review
DNA mismatch repair (MMR) maintains genome stability primarily by repairing DNA replication-associated mispairs. Because loss of MMR function increases the mutation frequency genome-wide, defects in this pathway predispose affected individuals to cancer. The genes encoding essential eukaryotic MMR activities have been identified, as the recombinant proteins repair 'naked' heteroduplex DNA in vitro. However, the reconstituted system is inactive on nucleosome-containing heteroduplex DNA, and it is not understood how MMR occurs in vivo. Recent studies suggest that chromatin organization, nucleosome assembly/disassembly factors and histone modifications regulate MMR in eukaryotic cells, but the complexity and importance of the interaction between MMR and chromatin remodeling has only recently begun to be appreciated. This article reviews recent progress in understanding the mechanism of eukaryotic MMR in the context of chromatin structure and dynamics, considers the implications of these recent findings and discusses unresolved questions and challenges in understanding eukaryotic MMR.
Topics: Chromatin; Chromatin Assembly and Disassembly; DNA Mismatch Repair; DNA Replication; Genomic Instability; Humans; Nucleic Acid Heteroduplexes; Nucleosomes
PubMed: 24767944
DOI: 10.1016/j.dnarep.2014.03.027 -
Cells May 2021We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type... (Review)
Review
We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on and human tumors. Well-studied organisms include and , while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring-parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, , , and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.
Topics: Cell Nucleus; DNA Damage; DNA Mismatch Repair; DNA Mutational Analysis; Genomic Instability; Humans; Mutation Rate; Whole Genome Sequencing
PubMed: 34067668
DOI: 10.3390/cells10051224