MOF-mediated acetylation of UHRF1 enhances UHRF1 E3 ligase activity to facilitate DNA methylation maintenance,Cell Reports

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MOF-mediated acetylation of UHRF1 enhances UHRF1 E3 ligase activity to facilitate DNA methylation maintenance
Cell Reports ( IF 7.5 ) Pub Date : 2024-03-05 , DOI: 10.1016/j.celrep.2024.113908
Linsheng Wang ₁ , Xi Yang ₂ , Kaiqiang Zhao ₃ , Shengshuo Huang ₂ , Yiming Qin ₄ , Zixin Chen ₄ , Xiaobin Hu ₂ , Guoxiang Jin ₅ , Zhongjun Zhou ₆

Affiliation

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.
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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.
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.
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 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; Orthopedic Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, P.R. China.

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.

中文翻译：

MOF介导的UHRF1乙酰化增强UHRF1 E3连接酶活性以促进DNA甲基化维持

多结构域蛋白 UHRF1（类泛素，包含 PHD 和环指结构域，1）在 DNA 复制过程中募集 DNMT1 来维持 DNA 甲基化。在这里，我们发现 MOF（第一个缺失的雄性）在 RING 前接头区域的 K670 处乙酰化 UHRF1，而 HDAC1 在同一位点使 UHRF1 去乙酰化。我们还发现，当 K670 突变时，K667 和 K668 也可以被 MOF 乙酰化。 UHRF1 中 MOF/HDAC1 介导的乙酰化受细胞周期调节，并在 G1/S 期达到峰值，这与 UHRF1 募集 DNMT1 维持 DNA 甲基化的功能一致。此外，UHRF1 乙酰化显着增强其 E3 连接酶活性。消除这些位点的 UHRF1 乙酰化会减弱 UHRF1 介导的 H3 泛素化，进而损害 DNMT1 募集和 DNA 甲基化。总而言之，这些发现确定 MOF 是 UHRF1 的乙酰转移酶，并定义了通过 MOF 介导的 UHRF1 乙酰化调节 DNA 甲基化维持的潜在机制。

更新日期：2024-03-05

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