Transcriptional Autoregulation by BRCA1

Abstract

The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult. Cancer Res; 70(2); 532-42. ©2010 AACR.

Transcriptional Upregulation of DNA Damage Response Genes in Bank Voles (Myodes glareolus) Inhabiting the Chernobyl Exclusion Zone

“…That p21 expression is not altered in animals inhabiting the CEZ implies cell cycle control pathways are not activated in response to increased Atm expression. Brca1 is upregulated in response to genotoxic stress (De Siervi et al, 2010). A lack of change in expression of Brca1 in bank voles from the CEZ indicates that the homologous recombination repair pathway is not a key component of the response to environmental radionuclides, consistent with a recent study of expression of DBS repair pathways during exposure to IR (Liu et al, 2016).…”

BRCA1 Loss Induces GADD153-Mediated Doxorubicin Resistance in Prostate Cancer

“…PC3 stable cell lines [pcDNA3, pcDNA3 BRCA1, short hairpin RNA (shRNA) scramble, and shRNA BRCA1] were previously described (19). Doxorubicin (Rontag S.A.) was prepared in dimethyl sulfoxide (DMSO).…”

“…PC3 cells were exposed to different treatments, lysed, and immunobloted as previously described (24), using antibodies against GADD153 (R20), BRCA1 (19), p21 WAF1/CIP1 (C-19), cyclin D1 (HD11), cyclin E (HE12), cyclin A (C-19), cyclin B1 (GNS1), Lamin A/C (636), and actin B (I19) proteins from Santa Cruz Biotechnology. Protein quantitation was determined by Image J 1.41 software.…”

“…cDNA was synthesized from 2 mg of RNA by using RevertAid First Strand (Fermentas). Quantitative PCR (qPCR) was carried out as previously described (19,25) Reporters PC3 cells were transiently transfected by using lipofectamine 2000 (Invitrogen) with 1 mg of GADD153 luciferase plasmid or cotransfected with 1 mg of pcDNA3. After 24 hours, cells were exposed to genotoxic agents as indicated (50 J/m 2 UV or 1 mmol/L doxorubicin), harvested, and lysed with 40 mL of Steady Glomax Luciferase System (Promega).…”

“…Finding target genes regulated by BRCA1 overexpression in human cell lines might give insight into genetic pathways disrupted in cells that have mutated BRCA1. It had been published that BRCA1 controls the transcription of several genes (16)(17)(18) including its own transcription (19,20). Understanding BRCA1 transcriptional targets and their functions will better explain the diverse role that BRCA1 plays in the control of DNA repair and cell-cycle progression.…”