MOF-mediated acetylation of UHRF1 enhances UHRF1 E3 ligase activity to facilitate DNA methylation maintenance
Linsheng Wang,
Xi Yang,
Kaiqiang Zhao,
Shengshuo Huang,
Yiming Qin,
Zixin Chen,
Xiaobin Hu,
Guoxiang Jin,
Zhongjun Zhou
Affiliations
Linsheng Wang
Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China; Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, P.R. China; School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
Xi Yang
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
Kaiqiang Zhao
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong; Dongguang Children’s Hospital, Dongguan Pediatric Research Institute, Dongguan, P.R. China
Shengshuo Huang
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
Yiming Qin
Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China; Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, P.R. China
Zixin Chen
Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China; Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, P.R. China
Xiaobin Hu
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
Guoxiang Jin
Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, P.R. China; Corresponding author
Zhongjun Zhou
Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, P.R. China; School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong; Orthopedic Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, P.R. China; Corresponding author
Summary: The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (males absent on the first) acetylates UHRF1 at K670 in the pre-RING linker region, whereas HDAC1 deacetylates UHRF1 at the same site. We also identify that K667 and K668 can also be acetylated by MOF when K670 is mutated. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity. Abolishing UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs DNMT1 recruitment and DNA methylation. Taken together, these findings identify MOF as an acetyltransferase for UHRF1 and define a mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.
