title: Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription.
abstract: Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression.
authors: Department of Biological Chemistry, School of Sciences (FCEN), University of Buenos Aires (UBA), CONICET, Buenos Aires, Argentina.
authors: Cristian
authors: C
authors: Moiola
authors: Paola
authors: P
authors: De Luca
authors: Javier
authors: J
authors: Cotignola
authors: Kevin
authors: K
authors: Gardner
authors: Elba
authors: E
authors: Vazquez
authors: Adriana
authors: A
authors: De Siervi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011753:Pyrones / Q000494:pharmacology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000903:Antibiotics, Antineoplastic; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D009025:Morpholines; D009687:Nuclear Proteins; D011753:Pyrones; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human