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MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.
- Source :
-
Journal of Experimental & Clinical Cancer Research (17569966) . 11/14/2023, Vol. 42 Issue 1, p1-19. 19p. - Publication Year :
- 2023
-
Abstract
- Background: Inherited defects in the base-excision repair gene MBD4 predispose individuals to adenomatous polyposis and colorectal cancer, which is characterized by an accumulation of C > T transitions resulting from spontaneous deamination of 5'-methylcytosine. Methods: Here, we have investigated the potential role of MBD4 in regulating DNA methylation levels using genome-wide transcriptome and methylome analyses. Additionally, we have elucidated its function through a series of in vitro experiments. Results: Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair. Transcriptome and methylome analyses reveal a genome-wide hypomethylation of promoters, gene bodies and repetitive elements in the absence of MBD4 in vivo. Methylation mark loss is accompanied by a broad transcriptional derepression phenotype affecting promoters and retroelements with low methylated CpG density. MBD4 in vivo forms a complex with the mismatch repair proteins (MMR), which exhibits high bi-functional glycosylase/AP-lyase endonuclease specific activity towards methylated DNA substrates containing a G/T mismatch. Experiments using recombinant proteins reveal that the association of MBD4 with the MMR protein MLH1 is required for this activity. Conclusions: Our data identify MBD4 as an enzyme specifically designed to repair deaminated 5-methylcytosines and underscores its critical role in safeguarding against methylation damage. Furthermore, it illustrates how MBD4 functions in normal and pathological conditions. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DNA methylation
*RECOMBINANT proteins
*COLORECTAL cancer
*DENSITY
*METHYLATION
Subjects
Details
- Language :
- English
- ISSN :
- 17569966
- Volume :
- 42
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Experimental & Clinical Cancer Research (17569966)
- Publication Type :
- Academic Journal
- Accession number :
- 173584758
- Full Text :
- https://doi.org/10.1186/s13046-023-02882-z