TY - JOUR
T1 - Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation
AU - Nishiyama, Atsuya
AU - Mulholland, Christopher B.
AU - Bultmann, Sebastian
AU - Kori, Satomi
AU - Endo, Akinori
AU - Saeki, Yasushi
AU - Qin, Weihua
AU - Trummer, Carina
AU - Chiba, Yoshie
AU - Yokoyama, Haruka
AU - Kumamoto, Soichiro
AU - Kawakami, Toru
AU - Hojo, Hironobu
AU - Nagae, Genta
AU - Aburatani, Hiroyuki
AU - Tanaka, Keiji
AU - Arita, Kyohei
AU - Leonhardt, Heinrich
AU - Nakanishi, Makoto
N1 - Funding Information:
We acknowledge the kind support of the beam line staff at the Photon Factory for X-ray data collection. We are grateful to En Li for providing wt J1 mESCs. We thank Martha Smets for the preparation of Dnmt1 KO and Uhrf1 KO samples. This study was supported by a PRESTO from JST (to K.A.), by MEXT/JSPS KAKENHI (JP26250027, JP22118003, JP16K15239, and JP19H05740 to M.N., JP18H02392 and JP19H05294 to K.A., JP15H01188, JP16H04818, and JP19H05285 to A.N., JP18H05498 to Y.S., JP26000014 to K.T), by the Research Program on Hepatitis of the Japan Agency for Medical Research and Development, and by an AMED grant (19cm0106134h0002) to M.N. H.L. acknowledges the support of the Deutsche Forschungsgemeinschaft (SFB1064/A17/A22 and SFB1243/A01). A.N. was supported in part by grants from the Naito Foundation and Mochida Memorial Foundation for Medical and Pharmaceutical Research.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-15006-4
DO - 10.1038/s41467-020-15006-4
M3 - Article
C2 - 32144273
AN - SCOPUS:85081532004
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1222
ER -