The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.
The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.
Strano
Sabrina
S
Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.
Monti
Olimpia
O
Pediconi
Natalia
N
Baccarini
Alessia
A
Fontemaggi
Giulia
G
Lapi
Eleonora
E
Mantovani
Fiamma
F
Damalas
Alexander
A
Citro
Gennaro
G
Sacchi
Ada
A
Del Sal
Giannino
G
Levrero
Massimo
M
Blandino
Giovanni
G
D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011506:Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C414742:P53AIP1 protein, human; D000071156:Promyelocytic Leukemia Protein; D011506:Proteins; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C456659:YY1AP1 protein, human; C070576:PML protein, human; D004317:Doxorubicin; D002945:Cisplatin