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DNA Repair Feb 2016MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these... (Review)
Review
MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these functions, DNA mismatch repair is the major one. The loss of MutLα abolishes DNA mismatch repair, thereby predisposing humans to cancer. MutLα has an endonuclease activity that is required for DNA mismatch repair. The endonuclease activity of MutLα depends on the DQHA(X)2E(X)4E motif which is a part of the active site of the nuclease. This motif is also present in many bacterial MutL and eukaryotic MutLγ proteins, DNA mismatch repair system factors that are homologous to MutLα. Recent studies have shown that yeast MutLγ and several MutL proteins containing the DQHA(X)2E(X)4E motif possess endonuclease activities. Here, we review the endonuclease activities of MutLα and its homologs in the context of DNA mismatch repair.
Topics: Animals; DNA Mismatch Repair; DNA Repair Enzymes; Endonucleases; Humans; Models, Biological; Sequence Homology, Amino Acid
PubMed: 26719141
DOI: 10.1016/j.dnarep.2015.11.023 -
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 -
Journal of Medical Genetics Jul 2022Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR)...
BACKGROUND
Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including , , and play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation-caused cancer. In the current study, we addressed the issue by using the Chinese population as a model.
METHODS
We performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population.
RESULTS
We identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral.
CONCLUSION
Our study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.
Topics: China; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Germ-Line Mutation; Humans; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Prevalence
PubMed: 34172528
DOI: 10.1136/jmedgenet-2021-107886 -
International Journal of Molecular... Aug 2020The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise... (Review)
Review
The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise and analyse published data on the associations between SNPs in mismatch repair genes and various cancers. The mismatch repair system plays a unique role in the control of the genetic integrity and it is often inactivated (germline and somatic mutations and hypermethylation) in cancer patients. Here, we focused on germline variants in mismatch repair genes and found the outcomes rather controversial: some SNPs are sometimes ascribed as protective, while other studies reported their pathological effects. Regarding the complexity of cancer as one disease, we attempted to ascertain if particular polymorphisms exert the effect in the same direction in the development and treatment of different malignancies, although it is still not straightforward to conclude whether polymorphisms always play a clear positive role or a negative one. Most recent and robust genome-wide studies suggest that risk of cancer is modulated by variants in mismatch repair genes, for example in colorectal cancer. Our study shows that rs1800734 in or rs2303428 in may influence the development of different malignancies. The lack of functional studies on many DNA mismatch repair SNPs as well as their interactions are not explored yet. Notably, the concerted action of more variants in one individual may be protective or harmful. Further, complex interactions of DNA mismatch repair variations with both the environment and microenvironment in the cancer pathogenesis will deserve further attention.
Topics: DNA Methylation; DNA Mismatch Repair; Disease Progression; Germ-Line Mutation; Humans; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasms; Polymorphism, Single Nucleotide
PubMed: 32756484
DOI: 10.3390/ijms21155561 -
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 -
Expert Reviews in Molecular Medicine Sep 2022Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions... (Review)
Review
Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions (increases) or contractions (decreases) in the number of repeat units. Some microsatellite instability (MSI) is seen at multiple STRs within a single cell and is associated with certain types of cancer. A second form of MSI is characterised by expansion of a single gene-specific STR and such expansions are responsible for a group of 40+ human genetic disorders known as the repeat expansion diseases (REDs). While the mismatch repair (MMR) pathway prevents genome-wide MSI, emerging evidence suggests that some MMR factors are directly involved in generating expansions in the REDs. Thus, MMR suppresses some forms of expansion while some MMR factors promote expansion in other contexts. This review will cover what is known about the paradoxical effect of MMR on microsatellite expansion in mammalian cells.
Topics: Animals; DNA Mismatch Repair; Genomic Instability; Humans; Mammals; Microsatellite Instability; Microsatellite Repeats
PubMed: 36059110
DOI: 10.1017/erm.2022.16 -
Neoplasia (New York, N.Y.) Sep 2023Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin....
Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pksE. coli signature (SBS88), reactive oxygen species (SBS17), and mismatch-repair deficiency (SBS44). A significant co-occurrence between MMRd SBS44 and pks-associated SBS88 signature was observed in a large cohort of human CRC patients (n=2,945), and significantly more SBS44 mutations were found when SBS88 was also detected. Collectively, these findings reveal the host response mechanisms underlying colibactin genotoxic activity and suggest that colibactin may exacerbate MMRd-associated mutations.
Topics: Humans; Mice; Animals; Mutagens; Escherichia coli; DNA Mismatch Repair; Mutation; Colorectal Neoplasms; Colonic Neoplasms
PubMed: 37499275
DOI: 10.1016/j.neo.2023.100918 -
The International Journal of... Nov 2023The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency... (Review)
Review
The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.
Topics: Humans; Immune Checkpoint Inhibitors; DNA Mismatch Repair; Biomarkers, Tumor; Microsatellite Instability; Colorectal Neoplasms
PubMed: 37862741
DOI: 10.1016/j.biocel.2023.106477 -
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