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

Hu, Fang; Zhu, Xiaoqiang; Yang, Haocheng; Oh, Jieun; Barbour, Jayne A.; Wong, Jason

doi:10.1126/sciadv.abg4398

Cited by 24 publications

(20 citation statements)

References 62 publications

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“…Our study identified three components (MSH2, MSH6 and PCNA) of the post-replicative MMR complex as ZFP57 interactors by LC–MS/MS analysis. The MMR pathway is essential for repairing 5mC deamination because the MSH2/MSH6 heterodimer recognizes G:T mismatches and recruits downstream proteins for correction [ 15 , 26 ]. Indeed, defects of MMR genes increase the genome-wide mutation rate of methylated CpGs in cancer [ 15 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The MMR pathway is essential for repairing 5mC deamination because the MSH2/MSH6 heterodimer recognizes G:T mismatches and recruits downstream proteins for correction [15,26]. Indeed, defects of MMR genes increase the genome-wide mutation rate of methylated CpGs in cancer [15,27]. Also, Msh2/Msh6 knockout mice show higher cancer predisposition, microsatellite instability and mutator phenotype [28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…The mismatch-repair (MMR) complex recognizes misincorporated bases in double-stranded DNA and is required to repair G:T mis-matches resulting from deamination of 5-methylcytosine (5mC) [ 15 ]. It is worth noting that mutations arising from unrepaired 5mC deamination events are prevalent in MMR-deficient cancers, particularly those deficient in the MutSα heterodimer that is composed by the MSH2-MSH6 heterodimer [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex

Acurzio

Cecere

Giaccari

et al. 2022

Epigenetics & Chromatin

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Background Imprinting Control Regions (ICRs) are CpG-rich sequences acquiring differential methylation in the female and male germline and maintaining it in a parental origin-specific manner in somatic cells. Despite their expected high mutation rate due to spontaneous deamination of methylated cytosines, ICRs show conservation of CpG-richness and CpG-containing transcription factor binding sites in mammalian species. However, little is known about the mechanisms contributing to the maintenance of a high density of methyl CpGs at these loci. Results To gain functional insights into the mechanisms for maintaining CpG methylation, we sought to identify the proteins binding the methylated allele of the ICRs by determining the interactors of ZFP57 that recognizes a methylated hexanucleotide motif of these DNA regions in mouse ESCs. By using a tagged approach coupled to LC–MS/MS analysis, we identified several proteins, including factors involved in mRNA processing/splicing, chromosome organization, transcription and DNA repair processes. The presence of the post-replicative mismatch-repair (MMR) complex components MSH2 and MSH6 among the identified ZFP57 interactors prompted us to investigate their DNA binding profile by chromatin immunoprecipitation and sequencing. We demonstrated that MSH2 was enriched at gene promoters overlapping unmethylated CpG islands and at repeats. We also found that both MSH2 and MSH6 interacted with the methylated allele of the ICRs, where their binding to DNA was mediated by the ZFP57/KAP1 complex. Conclusions Our findings show that the MMR complex is concentrated on gene promoters and repeats in mouse ESCs, suggesting that maintaining the integrity of these regions is a primary function of highly proliferating cells. Furthermore, the demonstration that MSH2/MSH6 are recruited to the methylated allele of the ICRs through interaction with ZFP57/KAP1 suggests a role of the MMR complex in the maintenance of the integrity of these regulatory regions and evolution of genomic imprinting in mammalian species.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex

Acurzio

Cecere

Giaccari

et al. 2022

Epigenetics & Chromatin

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“…H3K36me3 marks the gene bodies and exons of active genes in humans (F. Li et al 2013; Huang, Gu, and Li 2018; Fang et al 2021; Aymard et al 2014; Sun et al 2020), and reduced mutation rates in active genes, regions, and gene bodies, as a consequence, have been observed in humans and other animals (Moore et al 2021; Akdemir et al 2020; R. Li et al 2021; Katju et al 2022a; Supek and Lehner 2017).…”

Section: Introductionmentioning

confidence: 99%

“…That the localization of DNA repair proteins can drive such mutation biases has been well-established in humans (Supek and Lehner, 2015, 2017, 2019; Katju et al, 2022a; Foster et al, 2015). In vertebrates, H3K36me3 is targeted by PWWP domains in proteins contributing to homology-directed and mismatch repair, with H3K36me3 marking the gene bodies and exons of active genes (Li et al, 2013; Huang et al, 2018; Fang et al, 2021; Aymard et al, 2014; Sun et al, 2020). As predicted, reduced mutation rates in active genes, regions, and gene bodies have been observed in humans and other animals (Moore et al, 2021; Akdemir et al, 2020; Li et al, 2021; Katju et al, 2022b; Supek and Lehner, 2017).…”

Section: Introductionmentioning

confidence: 99%

The H3K4me1 histone mark recruits DNA repair to functionally constrained genomic regions in plants

Quiroz

Zhao

Carbonell‐Bejerano

et al. 2022

Preprint

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Mutation is the ultimate source of genetic variation in natural populations and crops. To study mechanisms determining mutation rate variation within plant genomes, we analyzed 43,483 de novo germline single base substitutions in 1,504 fast neutron mutation lines of the model rice cultivar Kitaake (Oryza sativa ssp japonica) (from Li et al. 2017). We find that, like previously observed for de novo germline mutations in Arabidopsis. thaliana, mutation rates are significantly lower in genomic regions marked by H3K4me1, a histone modification found in the gene bodies of actively expressed genes in plants. We also observed conservation in rice for PDS5C, a cohesion cofactor involved in the homology-directed repair pathway that in A. thaliana binds to H3K4me1 via its Tudor domain. By examining existing ChIP-seq data for PDS5C in A. thaliana, we find that it localizes to genome regions marked by H3K4me1: regions of low mutation rates, coding regions, essential genes, constitutively expressed genes, and genes under stronger purifying selection, mirroring mutation biases observed in rice as well. We searched the A. thaliana proteome for genes containing similar Tudor domains and found that they are significantly enriched for DNA repair functions (p<1×10-11), including the mismatch repair MSH6 gene (in both rice and A. thaliana ), suggesting the potential for multiple DNA repair pathways to specifically target gene bodies and essential genes through H3K4me1 reading. These findings inspire further research to characterize mechanisms that localize DNA repair via histone interactions, leading to hypomutation in functionally constrained regions and potentially tuning the evolutionary trajectories of plant genomes.

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Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Weijers,

Hirsch,

Bakhuizen

et al. 2024

Intl Journal of Cancer

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Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS‐spectrum (LSS) cancers, including high‐grade gliomas and colorectal cancer, causality has been supported by typical MMR‐related tumor characteristics, but for non‐LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non‐LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non‐LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR‐deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non‐LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.

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

Abstract: DNA mismatch repair is essential for protecting the human genome from damage induced by 5-methylcytosine deamination.

Cited by 24 publications

References 62 publications

The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex

The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex

The H3K4me1 histone mark recruits DNA repair to functionally constrained genomic regions in plants

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

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