Conserved Antagonism between JMJD2A/KDM4A and HP1γ during Cell Cycle Progression

被引：128

作者：

Black, Joshua C. ^{[1
,2
]}

Allen, Andrew ^{[1
,2
]}

Van Rechem, Capucine ^{[1
,2
]}

Forbes, Emily ^{[1
,2
]}

Longworth, Michelle ^{[1
,2
]}

Tschoep, Katrin ^{[1
,2
]}

Rinehart, Claire ^{[3
]}

Quiton, Jonathan ^{[4
]}

Walsh, Ryan ^{[1
,2
]}

Smallwood, Andrea ^{[5
]}

Dyson, Nicholas J. ^{[1
,2
]}

Whetstine, Johnathan R. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA

[3] Western Kentucky Univ, Dept Biol, Bowling Green, KY 42101 USA

[4] Western Kentucky Univ, Dept Math & Comp Sci, Bowling Green, KY 42101 USA

[5] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

来源：

MOLECULAR CELL | 2010年 / 40卷 / 05期

关键词：

HISTONE H3 LYSINE-9; BETA-GLOBIN LOCUS; PERICENTRIC HETEROCHROMATIN; CAENORHABDITIS-ELEGANS; DNA-REPLICATION; C-ELEGANS; MAMMALIAN-CELLS; FISSION YEAST; HP1; PROTEINS; S-PHASE;

D O I：

10.1016/j.molcel.2010.11.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1 gamma antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2(-/-) animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1 gamma and controlling chromatin accessibility.

引用

页码：736 / 748

页数：13

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