HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53.
In response to DNA damage, p53 undergoes post-translational modifications (including acetylation) that are critical for its transcriptional activity. However, the mechanism by which p53 acetylation is regulated is still unclear. Here, we describe an essential role for HLA-B-associated transcript 3 (Bat3)/Scythe in controlling the acetylation of p53 required for DNA damage responses. Depletion of Bat3 from human and mouse cells markedly impairs p53-mediated transactivation of its target genes Puma and p21. Although DNA damage-induced phosphorylation, stabilization, and nuclear accumulation of p53 are not significantly affected by Bat3 depletion, p53 acetylation is almost completely abolished. Bat3 forms a complex with p300, and an increased amount of Bat3 enhances the recruitment of p53 to p300 and facilitates subsequent p53 acetylation. In contrast, Bat3-depleted cells show reduced p53-p300 complex formation and decreased p53 acetylation. Furthermore, consistent with our in vitro findings, thymocytes from Bat3-deficient mice exhibit reduced induction of puma and p21, and are resistant to DNA damage-induced apoptosis in vivo. Our data indicate that Bat3 is a novel and essential regulator of p53-mediated responses to genotoxic stress, and that Bat3 controls DNA damage-induced acetylation of p53.
Sasaki
Toru
T
The Campbell Family Institute for Breast Cancer Research (CFIBCR), Ontario Cancer Institute (OCI), University Health Network, Toronto, Ontario M5G 2C1, Canada.
Gan
Eugene C
EC
Wakeham
Andrew
A
Kornbluth
Sally
S
Mak
Tak W
TW
Okada
Hitoshi
H
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D045325:HCT116 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D018832:Molecular Chaperones; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C092009:BAG6 protein, human