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Original Paper

Dynamic Coregulatory Complex Containing BRCA1, E2F1 and CtIP Controls ATM Transcription

Moiola C.1 · De Luca P.1 · Cotignola J.1 · Gardner K.2 · Vazquez E.1 · De Siervi A.1

Author affiliations

1Department of Biological Chemistry, School of Sciences (FCEN), University of Buenos Aires (UBA), CONICET, Buenos Aires,2Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD

Corresponding Author

Adriana De Siervi

Intendente Guiraldes 2160 Pab II, 2do piso, CM1, Departamento de Química Biológica

Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales

Universidad de Buenos Aires, Buenos Aires, C1428EGA (Argentina)

Tel. +5411-4576-3300, E-Mail adesiervi@qb.fcen.uba.ar

Related Articles for ""

Cell Physiol Biochem 2012;30:596-608

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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.

© 2012 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: June 26, 2012
Published online: July 27, 2012
Issue release date: August 2012

Number of Print Pages: 13
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: https://www.karger.com/CPB

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