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

Seong Joo Koo; Amaury E. Fernández-Montalván; Volker Badock; Christopher J. Ott; Simon J. Holton; Oliver von Ahsen; Joern Toedling; Sarah Vittori; James E. Bradner; Mátyás Gorjánácz

doi:10.18632/oncotarget.11855

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Research Papers:

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

Seong Joo Koo _, Amaury E. Fernández-Montalván, Volker Badock, Christopher J. Ott, Simon J. Holton, Oliver von Ahsen, Joern Toedling, Sarah Vittori, James E. Bradner and Mátyás Gorjánácz

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Oncotarget. 2016; 7:70323-70335. https://doi.org/10.18632/oncotarget.11855

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Abstract

Seong Joo Koo1, Amaury E. Fernández-Montalván1, Volker Badock1, Christopher J. Ott2,3,4, Simon J. Holton1, Oliver von Ahsen1, Joern Toedling1, Sarah Vittori2,3, James E. Bradner2,3,4,5, Mátyás Gorjánácz1

1Drug Discovery, Bayer Pharma AG, Berlin, Germany

2Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA

3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

4Department of Medicine, Harvard Medical School, Boston, MA, USA

5Present address: Novartis Institute for BioMedical Research, Cambridge, MA, USA

Correspondence to:

Seong Joo Koo, email: [email protected]

Mátyás Gorjánácz, email: [email protected]

Keywords: cancer, ATAD2, DNA replication, bromodomain, histone acetylation

Received: August 05, 2016 Accepted: August 21, 2016 Published: September 06, 2016

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.

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Research Papers:

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

Abstract