Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation.

Nature Communications
Atsuya NishiyamaMakoto Nakanishi

Abstract

Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.

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Citations

Jul 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Wendan RenJikui Song
Aug 28, 2020·Mediators of Inflammation·Liguo ZhuShenghong Zhang
May 10, 2020·Scientific Reports·Jesús Rafael Rodríguez-AguileraHéctor Hernández-Vargas
Oct 22, 2020·Scientific Reports·Motoko UnokiHiroyuki Sasaki
Dec 11, 2020·Nucleic Acids Research·Nataliya PetrykPierre-Antoine Defossez
Jan 24, 2021·Nature Communications·Mike V VanLacramioara Bintu
Feb 20, 2021·Journal of Cancer Research and Clinical Oncology·Mangala Hegde, Manjunath B Joshi
Dec 15, 2020·Trends in Biochemical Sciences·Robert M VaughanScott B Rothbart
Mar 28, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Xuan MingYingfeng Li
Apr 8, 2021·Fluids and Barriers of the CNS·Stephanie A IheziePeeyush Kumar Thankamani Pandit
Apr 17, 2021·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Yulong LiXiaojun Yang
Apr 20, 2021·Nucleic Acids Research·Soichiro KumamotoMakoto Nakanishi
May 5, 2021·Nature Communications·Wendan RenJikui Song
Jun 15, 2021·Trends in Genetics : TIG·Atsuya Nishiyama, Makoto Nakanishi
Sep 15, 2021·Technology in Cancer Research & Treatment·Cheng-You JiaDa Fu
Oct 6, 2021·Nature Reviews. Genetics·Sanne M Janssen, Matthew C Lorincz

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Methods Mentioned

BETA
pull-down
pull-downs
immunodepletion
immunoprecipitation
size-exclusion
X-ray
RRBS
Repli-seq
electrophoresis
PCR

Software Mentioned

PyMOL
ORIGIN
PHENIX
methylKit
SAngler
Proteome Discoverer
R scripts
Bowtie
Image J
Trim Galore

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