Phosphorylation of p53 by TAF1 Inactivates p53-Dependent Transcription in the DNA Damage Response

• DOI: 10.1016/j.molcel.2013.10.031
• Publication Date: 2013-11-27T16:07:28Z
• Authors: Yong Wu; Joy C. Lin; Landon G. Piluso; Joseph M. Dhahbi; Selene Bobadilla; Stephen R. Spindler; Xuan Liu
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Biomedical and clinical sciences; 572; Transcription, Genetic; 1.1 Normal biological development and functioning; 612; Medical and Health Sciences; Cell Line; Promoter Regions; 03 medical and health sciences; Adenosine Triphosphate; Genetic; Underpinning research; Genetics; 2.1 Biological and endogenous factors; Humans; Aetiology; Phosphorylation; Promoter Regions, Genetic; Molecular Biology; Cancer; Histone Acetyltransferases; TATA-Binding Protein Associated Factors; 0303 health sciences; Prevention; Health sciences; Cell Biology; Biological Sciences; Biological sciences; Transcription Factor TFIID; Biochemistry and Cell Biology; Generic health relevance; Tumor Suppressor Protein p53; Transcription; Developmental Biology; DNA Damage; Genome-Wide Association Study

While p53 activation has long been studied, the mechanisms by which its targets genes are restored to their preactivation state are less clear. We report here that TAF1 phosphorylates p53 at Thr55, leading to dissociation of p53 from the p21 promoter and inactivation of transcription late in the DNA damage response. We further show that cellular ATP level might act as a molecular switch for Thr55 phosphorylation on the p21 promoter, indicating that TAF1 is a cellular ATP sensor. Upon DNA damage, cells undergo PARP-1-dependent ATP depletion, which is correlated with reduced TAF1 kinase activity and Thr55 phosphorylation, resulting in p21 activation. As cellular ATP levels recover, TAF1 is able to phosphorylate p53 on Thr55, which leads to dissociation of p53 from the p21 promoter. ChIP-sequencing analysis reveals p53 dissociates from promoters genome wide as cells recover from DNA damage, suggesting the general nature of this mechanism.