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Oncotarget. 2016 Oct 25;7(43):70323-70335. doi: 10.18632/oncotarget.11855.

ATAD2 is an epigenetic reader of newly synthesized histone marks during DNA replication.

Author information

1
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
2
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Department of Medicine, Harvard Medical School, Boston, MA, USA.
5
Present address: Novartis Institute for BioMedical Research, Cambridge, MA, USA.

Abstract

ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly. Similar to ATAD2-depletion, ectopic expression of ATAD2 mutants that are deficient in binding to these di-acetylation marks resulted in reduced DNA replication and impaired loading of PCNA onto chromatin, suggesting relevance of ATAD2 in DNA replication. Taken together, our data show a novel function of ATAD2 in cancer and for the first time identify a reader of newly synthesized histone di-acetylation-marks during replication.

KEYWORDS:

ATAD2; DNA replication; bromodomain; cancer; histone acetylation

PMID:
27612420
PMCID:
PMC5342555
DOI:
10.18632/oncotarget.11855
[Indexed for MEDLINE]
Free PMC Article

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