ATAD2 is an epigenetic reader of newly synthesized histone marks during DNA replication.
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.
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Seong Joo
SJ
Koo
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Amaury E
AE
Fernández-Montalván
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Volker
V
Badock
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
Christopher J
CJ
Ott
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Simon J
SJ
Holton
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Oliver
O
von Ahsen
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Joern
J
Toedling
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Sarah
S
Vittori
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Present address: Novartis Institute for BioMedical Research, Cambridge, MA, USA.
James E
JE
Bradner
Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Mátyás
M
Gorjánácz
D000074183:ATPases Associated with Diverse Cellular Activities / Q000502:physiology*; D000107:Acetylation; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology*; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D042421:Histone Code; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans
D004268:DNA-Binding Proteins; D006657:Histones; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
ATAD2; DNA replication; bromodomain; cancer; histone acetylation