BRCA1 orchestrates a novel molecular interplay at the BRCA1 and GADD153 promoters to regulate transcriptional responses to DNA damage.

DE LUCA P; VAZQUEZ ES; MOIOLA C; GUERON G; ZALAZAR F; GARDNER K; DE SIERVI A

Denver, USA

Congreso; ANNUAL MEETING AMERICAN ASSOCIATION FOR CANCER RESEARCH AACR CENTENNIAL; 2009

American Association for Cancer Research (AACR)

The BRCA1 gene product plays numerous roles in regulating genome integrity. It interacts with crucial proteins and is considered a gene-specific transcriptional co-regulator; however, BRCA1 role in the transcriptional response to DNA damage is poorly understood. By chromatin immunoprecipitation and genome arrays technology (ChIP-chip) we recently determined that BRCA1 is highly enriched at the BRCA1 promoter in cancer cells where it negative influences BRCA1 transcription. Following exposure to genotoxic agents, BRCA1 is released from it own promoter in order to be recruited to other genes or sites of DNA damage, as GADD153 (growth arrest and DNA damage gene). In this study, using Tandem ChIP, we show that the mechanism underlying BRCA1 auto-regulation involves the E2F1 transcription factor. BRCA1 release from its own promoter is accompanied by a reciprocal increase in its occupancy at the GADD153 promoter and an increase in GADD153 transcription. This transcriptional interplay is associated with increases in both BRCA1 and GADD153 transcription and GADD153-mediated apoptosis. Enforced BRCA1 expression enhances GADD153 mediate transcription and BRCA1 depletion silences both active BRCA1 transcription and GADD153 expression. These results describe a novel molecular interplay where BRCA1 and GADD153 show coordinate upregulation through rapid promoter exchange of BRCA1 protein in response to genotoxic stress.