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BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair

Abstract

Inheritance of a mutation in the gene BRCA1 confers on women a 50–85% lifetime risk of developing breast cancer1,2. 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 genome4,5,6. 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.

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Figure 1: Tetracycline-regulated expression of BRCA1 protein in p53-wildtype UBR60 and p53-deficient E621 cells and UV-inducible expression of wildtype p53 protein.
Figure 2: Effect of overexpression of BRCA1 on GGR in p53-deficient and p53-wildtype cells.
Figure 3: Effect of overexpression of BRCA1 on strand-specific repair in p53-deficient E621 and p53-wildtype UBR60 cells.
Figure 4: Overexpression of BRCA1 induces expression of DDB2 and GADD45 mRNA in p53-wildtype and p53-deficient cells.
Figure 5: Overexpression of BRCA1 induces expression of XPC but not XPA in p53-wildtype and p53-deficient cells.
Figure 6: A model for the involvement of BRCA1 and TP53 in NER in BRCA1-deficient breast cancers.

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Acknowledgements

We thank P. Hanawalt, A. Ganesan, F. Stockdale, C. Lopez and members of the Ford Laboratory for helpful discussions and critical reading of the manuscript, and I. Cross for expert technical assistance. This work was supported in part by a National Institutes of Health R01 Award, a Sidney Kimmel Foundation for Cancer Research Scholar Award and a Burroughs Wellcome Fund New Investigator Award in Toxicological Sciences (to J.M.F.). A.R.H. is an ASCO Clinical Scholar and is supported by the California Breast Cancer Research Program.

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Correspondence to James M. Ford.

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Hartman, AR., Ford, J. BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet 32, 180–184 (2002). https://doi.org/10.1038/ng953

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