Transcriptional regulation of the base excision repair pathway by BRCA1.
Inactivation of the breast cancer susceptibility gene BRCA1 plays a significant role in the development of a subset of breast cancers, although the major tumor suppressor function of this gene remains unclear. Previously, we showed that BRCA1 induces antioxidant-response gene expression and protects cells against oxidative stress. We now report that BRCA1 stimulates the base excision repair pathway, a major mechanism for the repair of oxidized DNA, by stimulating the activity of key base excision repair (BER) enzymes, including 8-oxoguanine DNA glycosylase (OGG1), the DNA glycosylase NTH1, and the apurinic endonuclease redox factor 1/apurinic endonuclease 1 (REF1/APE1), in human breast carcinoma cells. The increase in BER enzyme activity appears to be due, primarily, to an increase in enzyme expression. The ability of BRCA1 to stimulate the expression of the three BER enzymes and to enhance NTH1 promoter activity was dependent upon the octamer-binding transcription factor OCT1. Finally, we found that OGG1, NTH1, and REF1/APE1 each contribute to the BRCA1 protection against oxidative stress due to hydrogen peroxide and that hydrogen peroxide stimulates the expression of BRCA1 and the three BER enzymes. These findings identify a novel mechanism through which BRCA1 may regulate the repair of oxidative DNA damage.
Saha
Tapas
T
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Rih
Jeong Keun
JK
Roy
Rabindra
R
Ballal
Rahul
R
Rosen
Eliot M
EM
D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D051379:Mice; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human