Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

被引：59

作者：

Ren, Wendan ^{[1
]}

Fan, Huitao ^{[2
,3
]}

Grimm, Sara A. ^{[4
]}

Guo, Yiran ^{[2
,3
]}

Kim, Jae Jin ^{[5
]}

Yin, Jiekai ^{[6
]}

Li, Linhui ^{[1
]}

Petell, Christopher J. ^{[2
,3
]}

Tan, Xiao-Feng ^{[1
]}

Zhang, Zhi-Min ^{[1
,14
]}

Coan, John P. ^{[7
]}

Gao, Linfeng ^{[6
]}

Cai, Ling ^{[2
,3
]}

Detrick, Brittany ^{[1
]}

Cetin, Burak ^{[8
]}

Cui, Qiang ^{[9
,10
,11
]}

Strahl, Brian D. ^{[2
,3
]}

Gozani, Or ^{[7
]}

Wang, Yinsheng ^{[6
,12
]}

Miller, Kyle M. ^{[5
]}

O'Leary, Sean E. ^{[1
,8
]}

Wade, Paul A. ^{[4
]}

Patel, Dinshaw J. ^{[13
]}

Wang, Gang Greg ^{[2
,3
]}

Song, Jikui ^{[1
,6
]}

机构：

[1] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA

[2] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[4] NIEHS, Div Intramural Res, Epigenet & Stem Cell Biol Lab, Durham, NC 27709 USA

[5] Univ Texas Austin, LIVESTRONG Canc Inst, Inst Cellular & Mol Biol, Dept Mol Biosci,Dell Med Sch, Austin, TX 78712 USA

[6] Univ Calif Riverside, Environm Toxicol Grad Program, Riverside, CA 92521 USA

[7] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[8] Univ Calif Riverside, Cell Mol & Dev Biol Grad Program, Riverside, CA 92521 USA

[9] Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA

[10] Boston Univ, Dept Phys, 590 Commonwealth Ave, Boston, MA 02215 USA

[11] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA

[12] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA

[13] Mem Sloan Kettering Canc Ctr, Struct Biol Program, 1275 York Ave, New York, NY 10021 USA

[14] Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat &, Chinese Minist Educ MOE, Guangzhou 510632, Peoples R China

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 31期

关键词：

DNA methylation; H3K9me3; DNMT1; allosteric regulation; STRUCTURAL INSIGHT; EPIGENETIC INHERITANCE; MECHANISTIC INSIGHTS; METHYLTRANSFERASE; TANDEM TUDOR; HISTONE; DNMT1; UHRF1; PROTEIN; ACTIVATION;

D O I：

10.1073/pnas.2009316117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

引用

页码：18439 / 18447

页数：9

共 59 条

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