Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Deficiency of replication-independent DNA mismatch repair drives a 5-methylcytosine deamination mutational signature in cancer

ABSTRACT: Description DNA mismatch repair is essential for protecting the human genome from damage induced by 5-methylcytosine deamination. Multiple mutational signatures have been associated with DNA mismatch repair (MMR)–deficient cancers, but the mechanisms underlying their origin remain unclear. Here, using mutation data from cancer genomes, we identify a previously unknown function of MMR that is able to protect genomes from 5-methylcytosine (5mC) deamination–induced somatic mutations in a replication-independent manner. Cancers with deficiency of MMR proteins MSH2/MSH6 (MutSα) exhibit mutational signature contributions distinct from those that are deficient in MLH1/PMS2 (MutLα). This disparity arises from unrepaired 5mC deamination–induced mismatches rather than replicative DNA polymerase errors. In cancers with biallelic loss of MBD4 DNA glycosylase, repair of 5mC deamination damage is strongly associated with H3K36me3 chromatin, implicating MutSα as the essential factor in its repair. We thus uncover a noncanonical role of MMR in the protection against 5mC deamination–induced mutation in human cancers.

SUBMITTER: Fang H

PROVIDER: S-EPMC8565909 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

DNA cytosine and methylcytosine deamination by APOBEC3B: enhancing methylcytosine deamination by engineering APOBEC3B.

Project description:APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like) is a family of enzymes that deaminates cytosine (C) to uracil (U) on nucleic acid. APOBEC3B (A3B) functions in innate immunity against intrinsic and invading retroelements and viruses. A3B can also induce genomic DNA mutations to cause cancer. A3B contains two cytosine deaminase domains (CD1, CD2), and there are conflicting reports about whether both domains are active. Here we demonstrate that only CD2 of A3B (A3BCD2) has C deamination activity. We also reveal that both A3B and A3BCD2 can deaminate methylcytosine (mC). Guided by structural and functional analysis, we successfully engineered A3BCD2 to gain over two orders of magnitude higher activity for mC deamination. Important determinants that contribute to the activity and selectivity for mC deamination have been identified, which reveals that multiple elements, rather than single ones, contribute to the mC deamination activity and selectivity in A3BCD2 and possibly other APOBECs.

| S-EPMC4613526 | biostudies-literature

Corrigendum: Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers

Project description: Not available

| S-EPMC6724680 | biostudies-literature

Mutational signatures of DNA mismatch repair deficiency in <i>C. elegans</i> and human cancers.

Project description:Throughout their lifetime, cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. Although it is possible to associate mutational signatures extracted from human cancers with possible mutational processes, the exact causation is often unknown. Here, we use C. elegans genome sequencing of pms-2 and mlh-1 knockouts to reveal the mutational patterns linked to C. elegans MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit pole-4 Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the C. elegans MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and C. elegans MMR deficiency is the lack of elevated levels of NCG > NTG mutations in C. elegans, likely caused by the absence of cytosine (CpG) methylation in worms. The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

| S-EPMC5932607 | biostudies-literature

Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer.

Project description:Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Mutational characteristics of NER-deficiency may reveal important diagnostic opportunities, as tumors deficient in NER are more sensitive to certain treatments. Here, we analyzed the genome-wide somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1 -/Δ mice. Our results indicate that NER-deficiency increases the base substitution load twofold in liver but not in small intestinal ASCs, which coincides with the tissue-specific aging pathology observed in these mice. Moreover, NER-deficient ASCs of both tissues show an increased contribution of Signature 8 mutations, which is a mutational pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the base substitutions indicates that deficiency of global-genome NER (GG-NER) underlies the observed mutational consequences. In line with this, we observe increased Signature 8 mutations in a GG-NER-deficient human organoid culture, in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations could therefore contribute to a predictor of NER-deficiency based on a patient's mutational profile.

| S-EPMC6633256 | biostudies-literature

Unexplained mismatch repair deficiency: Case closed.

Project description:To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.

| S-EPMC9823207 | biostudies-literature

Single-Cell Sequencing of Mouse Thymocytes Reveals Mutational Landscape Shaped by Replication Errors, Mismatch Repair, and H3K36me3.

Project description:DNA mismatch repair (MMR) corrects replication errors and is recruited by the histone mark H3K36me3, enriched in exons of transcriptionally active genes. To dissect in vivo the mutational landscape shaped by these processes, we employed single-cell exome sequencing on T cells of wild-type and MMR-deficient (Mlh1-/-) mice. Within active genes, we uncovered a spatial bias in MMR efficiency: 3' exons, often H3K36me3-enriched, acquire significantly fewer MMR-dependent mutations compared with 5' exons. Huwe1 and Mcm7 genes, both active during lymphocyte development, stood out as mutational hotspots in MMR-deficient cells, demonstrating their intrinsic vulnerability to replication error in this cell type. Both genes are H3K36me3-enriched, which can explain MMR-mediated elimination of replication errors in wild-type cells. Thus, H3K36me3 can boost MMR in transcriptionally active regions, both locally and globally. This offers an attractive concept of thrifty MMR targeting, where critical genes in each cell type enjoy preferential shielding against de novo mutations.

| S-EPMC7474001 | biostudies-literature

Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential.

Project description:BackgroundMismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management.MethodsWe tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load.ResultsFifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours.ConclusionsNext-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.

| S-EPMC9130322 | biostudies-literature

Exonuclease 1-dependent and independent mismatch repair.

Project description:DNA mismatch repair (MMR) acts to repair mispaired bases resulting from misincorporation errors during DNA replication and also recognizes mispaired bases in recombination (HR) intermediates. Exonuclease 1 (Exo1) is a 5' → 3' exonuclease that participates in a number of DNA repair pathways. Exo1 was identified as an exonuclease that participates in Saccharomyces cerevisiae and human MMR where it functions to excise the daughter strand after mispair recognition, and additionally Exo1 functions in end resection during HR. However, Exo1 is not absolutely required for end resection during HR in vivo. Similarly, while Exo1 is required in MMR reactions that have been reconstituted in vitro, genetics studies have shown that it is not absolutely required for MMR in vivo suggesting the existence of Exo1-independent and Exo1-dependent MMR subpathways. Here, we review what is known about the Exo1-independent and Exo1-dependent subpathways, including studies of mutations in MMR genes that specifically disrupt either subpathway.

| S-EPMC4522362 | biostudies-literature

Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks.

Project description:DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.

| S-EPMC4141275 | biostudies-literature

The Somatic Mutational Landscape of Mismatch Repair Deficient Prostate Cancer.

Project description:Prostate cancers with mismatch repair deficiency (MMR-d) have aggressive clinical and histological features, and they are potentially responsive to immunotherapy. However, its rarity prevents the analysis of the underlying biology. Here, we collected the genomic data of 2664 primary prostate tumors and 1409 metastatic prostate tumors from the GENIE and TCGA databases. A total of 69 (2.59%) primary and 60 (4.26%) metastatic MMR-d tumors were identified among these tumors. Single nucleotide variant (SNV) frequencies of 34 candidate genes (including KMT2D (46.4%), ZFHX3 (33.3%), JAK1 (31.9%), and RNF43 (27.5%)) and 16 candidate genes (including KMT2D (33.3%) and JAK1 (28.3%)) were higher in MMR-d primary tumors and MMR-d metastatic tumors, respectively. The tumor mutation burden (TMB) was higher in primary MMR-d tumors. Homozygous deletions of EPCAM and EPAS1 were enriched in MMR-d primary tumors, while EPCAM deletions were enriched in metastatic MMR-d tumors. For genomic rearrangement events, TMPRSS2-ETS fusions were less frequent in primary MMR-d tumors. Our study indicates MMR-d prostate cancers have unique genomic features. These may play an important role in providing therapeutic targets for the treatment of this subset of prostate cancer patients.

| S-EPMC9864094 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data