RFTS ‐dependent negative regulation of Dnmt1 by nucleosome structure and histone tails
Yuichi Mishimaa b✉, Laura Bruecknera b, Saori Takahashia b, Toru Kawakamic d, Kyohei Aritae f, Shota Okaa b, Junji Otania b, Hironobu Hojoc d, Masahiro Shirakawag h i j, Akira Shinoharak l, Mikio Watanabem n, Isao Suetakea b g i m n o p✉
- aLaboratory of Epigenetics Institute for Protein Research Osaka University Suita Japan
- bLaboratory of Epigenetics, Institute for Protein Research, Osaka University, Suita, Japan
- cLaboratory of Organic Chemistry Institute for Protein Research Osaka University Suita Japan
- dLaboratory of Organic Chemistry, Institute for Protein Research, Osaka University, Suita, Japan
- eDivision of Macromolecular Crystallography Graduate School of Nanobioscience Yokohama City University Japan
- fDivision of Macromolecular Crystallography, Graduate School of Nanobioscience, Yokohama City University, Japan
- gCREST Japan Science and Technology Agency Saitama Japan
- hDepartment of Molecular Engineering Graduate School of Engineering Kyoto University Japan
- iCREST, Japan Science and Technology Agency, Saitama, Japan
- jDepartment of Molecular Engineering, Graduate School of Engineering, Kyoto University, Japan
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Abstract
DNA methylation in promoter regions represses gene expression and is copied over mitotic divisions by Dnmt1. Dnmt1 activity is regulated by its replication foci targeting sequence (RFTS) domain which masks the catalytic pocket. It has been shown that Dnmt1 activity on unmethylated DNA is inhibited in nucleosome cores. In the present study, we aimed to assess the effect of nuclesome formation on maintenance methylation at single CpG resolution. We show that Dnmt1 fully methylates naked linker DNA in dinucleosomes, whereas maintenance methylation was repressed at all CpG sites in nucleosome core particles. Deletion of RFTS partly released obstruction of Dnmt1 activity in core particles. Histone H3 tail peptides inhibited Dnmt1 in an RFTS-dependent manner and repression was modulated by acetylation or methylation. We propose a novel function of RFTS to regulate Dnmt1 activity in nucleosomes.
TL;DRIt is shown that Dnmt1 fully methylates naked linker DNA in dinucleosomes, whereas maintenance methylation was repressed at all CpG sites in nucleosome core particles. (Semantic Scholar)