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Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes (CUT&RUN)

ABSTRACT: Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to the spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to active chromatin and early replicating DNA, which correlates with lower mutational burden in these domains. We validate our findings by modeling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275181 | GEO | 2024/09/12

REPOSITORIES: GEO

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MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.

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2022-01-10 | GSE84497 | GEO

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Single-step deamination sequencing of 5-hydroxymethylcytosine in genomic DNA at single-base resolution

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Expression data from control and Mbd4 KO CH12 cells that were activated with CIT for 24 hours.

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2013-12-19 | E-GEOD-51559 | biostudies-arrayexpress

CpG island-specific demethylation pathway in ES cells

Project description:Following erasure in the early animal embryo, a new bimodal DNA methylation pattern is regenerated at the time of implantation in each individual through a wave of generalized de novo modification with CpG islands specifically left unmethylated. In this paper, we ask whether CpG islands are M-bM-^@M-^\protectedM-bM-^@M-^] from de novo methylation or, alternatively, acquire their unmodified state through M-bM-^@M-^\demethylation.M-bM-^@M-^] Using a genetic approach, we demonstrate that ES cells indeed have the ability to specifically demethylate CpG islands through pathways involving hydroxymethylation (Tet1), deamination (Aid), glycosylation (Mbd4) and excision repair (Gadd45a) genes. Surprisingly, this demethylation system is not actually necessary for generating the overall bimodal methylation pattern in ES cells. This general activity does, however, appear to be involved both in somatic cell reprogramming, as well as the normal methylation reprogramming that takes place in the early embryo. CpG-methylated genomic DNA was enriched using a methyl-DNA immunoprecipitation (mDIP) assay. DNA from the input and bound (enriched) DNA for each sample were labeled and hybridized on the array to define the methylation state of each region.

2013-11-17 | E-GEOD-48923 | biostudies-arrayexpress

Expression data from control and Mbd4 KO CH12 cells that were activated with CIT for 24 hours.

2013-12-19 | GSE51559 | GEO

CpG island-specific demethylation pathway in ES cells

Project description:Following erasure in the early animal embryo, a new bimodal DNA methylation pattern is regenerated at the time of implantation in each individual through a wave of generalized de novo modification with CpG islands specifically left unmethylated. In this paper, we ask whether CpG islands are “protected” from de novo methylation or, alternatively, acquire their unmodified state through “demethylation.” Using a genetic approach, we demonstrate that ES cells indeed have the ability to specifically demethylate CpG islands through pathways involving hydroxymethylation (Tet1), deamination (Aid), glycosylation (Mbd4) and excision repair (Gadd45a) genes. Surprisingly, this demethylation system is not actually necessary for generating the overall bimodal methylation pattern in ES cells. This general activity does, however, appear to be involved both in somatic cell reprogramming, as well as the normal methylation reprogramming that takes place in the early embryo.

2013-11-17 | GSE48923 | GEO

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2023-06-19 | GSE234235 | GEO

Gene expression analysis of B cell lymphomas from representative IÂµHABcl6, IÂµHABcl6 Ung-/- Msh2-/-, and IÂµHABcl6 Msh2-/- mouse models.

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