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Mol Cell. 2010 Dec 10;40(5):736-48. doi: 10.1016/j.molcel.2010.11.008.

Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression.

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1
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, 13th Street, Charlestown, MA 02129, USA.

Abstract

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 HP1γ 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 HP1γ and controlling chromatin accessibility.

PMID:
21145482
DOI:
10.1016/j.molcel.2010.11.008
[Indexed for MEDLINE]
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