CBP/p300-mediated acetylation of histone H3 on lysine 56.
Acetylation within the globular core domain of histone H3 on lysine 56 (H3K56) has recently been shown to have a critical role in packaging DNA into chromatin following DNA replication and repair in budding yeast. However, the function or occurrence of this specific histone mark has not been studied in multicellular eukaryotes, mainly because the Rtt109 enzyme that is known to mediate acetylation of H3K56 (H3K56ac) is fungal-specific. Here we demonstrate that the histone acetyl transferase CBP (also known as Nejire) in flies and CBP and p300 (Ep300) in humans acetylate H3K56, whereas Drosophila Sir2 and human SIRT1 and SIRT2 deacetylate H3K56ac. The histone chaperones ASF1A in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF-1 (chromatin assembly factor 1) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. We show that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumours. Our identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation and cancer.
Das
Chandrima
C
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, PO Box 6511, Aurora Colorado 80045, USA.
Lucia
M Scott
MS
Hansen
Kirk C
KC
Tyler
Jessica K
JK
D000107:Acetylation; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D056505:Retinoblastoma-Binding Protein 4; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
C110251:Caf1-55 protein, Drosophila; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D006657:Histones; D018832:Molecular Chaperones; D056505:Retinoblastoma-Binding Protein 4; C491642:asf1 protein, Drosophila; C524696:nej protein, Drosophila; D050880:p300-CBP Transcription Factors; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; C447899:Sirt2 protein, Drosophila; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine