BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair.
Inheritance of a mutation in the gene BRCA1 confers on women a 50-85% lifetime risk of developing breast cancer. Mutations in the TP53 tumor-suppressor gene are found in 70-80% of BRCA1-mutated breast cancer but only 30% of those with wildtype BRCA1 (ref. 3). The p53 protein regulates nucleotide excision repair (NER) through transcriptional regulation of genes involved in the recognition of adducts in genomic DNA. Loss of p53 function results in deficient global genomic repair (GGR), a subset of NER that targets and removes lesions from the whole genome. Here we show that BRCA1 specifically enhances the GGR pathway, independent of p53, and can induce p53-independent expression of the NER genes XPC, DDB2, and GADD45. Defects in the NER pathway in BRCA1-associated breast cancers may be causal in tumor development, suggesting a multistep model of carcinogenesis.
Hartman
Anne-Renee
AR
Department of Internal Medicine (Oncology), Stanford University Medical Center, Stanford, California 94305-5151, USA.
Ford
James M
JM
D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008957:Models, Genetic; D011506:Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C117669:DDB2 protein, human; C086984:XPC protein, human