Mammalian DNA maintenance methylation depends on histone but not PAF15 ubiquitination.
8 affiliations
- 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
- 2Joint Center for Translational Medicine, Fengxian District Central Hospital, Shanghai, China.
- 3State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
- 4International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
- 5Institute of Biochemistry and Biophysics, Warsaw, Poland.
- 6Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
- 7Joint Center for Translational Medicine, Fengxian District Central Hospital, Shanghai, China. [email protected].
- 8Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
Abstract
In mammals, DNA methylation is an essential inheritable epigenetic modification maintained by the DNMT1-UHRF1 machinery in a UHRF1 E3 ubiquitin ligase-activity-dependent manner. UHRF1-catalyzed histone ubiquitination and PAF15 ubiquitination have been proposed to recruit DNMT1 to hemi-methylated CpGs. Here, we confirm that both PAF15 and histone H3 are robustly ubiquitinated by UHRF1 in a replication-dependent manner during S phase. However, loss of PAF15 or its ubiquitination, or overexpression of ubiquitination-deficient PAF15, does not alter DNMT1 recruitment to replicating DNA or global DNA methylation. Notably, the DNMT1 inhibitor GSK-3685032 strongly enhances histone ubiquitination, likely via UHRF1 activation driven by accumulated hemi-methylated CpGs, but markedly reduces PAF15 ubiquitination. We show that UHRF1-mediated PAF15 ubiquitination requires DNMT1, is strictly replication-coupled, and that PAF15 and histone ubiquitination are mediated by distinct UHRF1 pools. Taken together, our study demonstrates that hemi-methylated-DNA-stimulated local histone ubiquitination, rather than replication-coupled PAF15 ubiquitination, drives DNMT1 targeting for maintenance methylation.
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BibTeX
@article{li2026mammalian,
title = {{Mammalian DNA maintenance methylation depends on histone but not PAF15 ubiquitination.}},
author = {Jialun Li and Yuanyong Huang and Meilin Sun and Shaoqi Zheng and Fenghua Chen and Xingrui Song and Weiyi Lai and Yanling Yao and Zhaosu Chen and Hailin Wang and Jiwen Li and Matthias Bochtler and Jiemin Wong},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77759-8},
url = {https://europepmc.org/article/MED/42897165},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Mammalian DNA maintenance methylation depends on histone but not PAF15 ubiquitination.
AU - Jialun Li
AU - Yuanyong Huang
AU - Meilin Sun
AU - Shaoqi Zheng
AU - Fenghua Chen
AU - Xingrui Song
AU - Weiyi Lai
AU - Yanling Yao
AU - Zhaosu Chen
AU - Hailin Wang
AU - Jiwen Li
AU - Matthias Bochtler
AU - Jiemin Wong
PY - 2026
DA - 2026/09/17
JO - Nature communications
DO - 10.1038/s41467-026-77759-8
UR - https://europepmc.org/article/MED/42897165
AB - In mammals, DNA methylation is an essential inheritable epigenetic modification maintained by the DNMT1-UHRF1 machinery in a UHRF1 E3 ubiquitin ligase-activity-dependent manner. UHRF1-catalyzed histone ubiquitination and PAF15 ubiquitination have been proposed to recruit DNMT1 to hemi-methylated CpGs. Here, we confirm that both PAF15 and histone H3 are robustly ubiquitinated by UHRF1 in a replication-dependent manner during S phase. However, loss of PAF15 or its ubiquitination, or overexpression of ubiquitination-deficient PAF15, does not alter DNMT1 recruitment to replicating DNA or global DNA methylation. Notably, the DNMT1 inhibitor GSK-3685032 strongly enhances histone ubiquitination, likely via UHRF1 activation driven by accumulated hemi-methylated CpGs, but markedly reduces PAF15 ubiquitination. We show that UHRF1-mediated PAF15 ubiquitination requires DNMT1, is strictly replication-coupled, and that PAF15 and histone ubiquitination are mediated by distinct UHRF1 pools. Taken together, our study demonstrates that hemi-methylated-DNA-stimulated local histone ubiquitination, rather than replication-coupled PAF15 ubiquitination, drives DNMT1 targeting for maintenance methylation.
SN - 2041-1723
ER -