Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage.
E2F1, a member of the E2F family of transcription factors, plays a pivotal role in controlling both physiological cell-cycle progression and apoptotic cell death in response to DNA damage and oncogene activation. In response to genotoxic stresses, E2F1 is stabilized by signals that include ATM-dependent phosphorylation. We recently demonstrated that DNA damage induces also E2F1 acetylation, which is required for its recruitment onto apoptotic gene promoters. Here we show that E2F1 is stabilized in response to doxorubicin and cisplatin treatments even in the absence of either ATM-dependent phosphorylation or p53 and cAbl, two major transducers of DNA damage signaling. We found that acetylation of E2F1 is, instead, required to stabilize the protein in response to doxorubicin. Finally, we report that the formation of E2F1-p300/CREB-binding protein-associated factor (P/CAF) complexes is preferentially induced in doxorubicin-treated cells, and that P/CAF acetyltransferase (HAT), but not p300 HAT activity, is required for a significant E2F1 stabilization and accumulation. Our results unveil a differential role of P/CAF and p300 in acetylation-induced stabilization of E2F1, thus supporting a specific role for P/CAF HAT activity in E2F1-dependent apoptosis in response to DNA damage.
Ianari
Alessandra
A
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, 00161 Rome, Italy.
Gallo
Rita
R
Palma
Marzia
M
Alesse
Edoardo
E
Gulino
Alberto
A
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051548:Histone Acetyltransferases; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002945:Cisplatin; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051548:Histone Acetyltransferases; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse