To investigate the molecular basis by which the loss of 53BP1 suppressed Brca1-associated mammary tumor formation, the researchers undertook a series of experiments using mouse cells grown in culture. These experiments showed that it was possible to restore HR to Brca1-deficient cells by inactivation of the gene 53BP1.
Further analysis led to a model in which both Brca1 and 53BP1 are capable of binding to replication-associated chromosome breaks. According to this model, when both proteins are present, Brca1 displaces 53BP1, the HR machinery has full access to the breaks, and HR proceeds. In Brca1-deficient cells, the binding of 53BP1 to the site of DNA damage interferes with the activity of HR proteins. Consequently, the damage is instead repaired by an alternative mutagenic pathway that promotes cancer. When 53BP1 is absent, Brca1 is not needed to displace it. Therefore, HR can take place normally when both proteins are missing.
Our results show that the choice of pathway used to repair DNA damage determines whether the repair is error-free or error-prone. This opens the possibility of using drugs to inhibit mutagenic DNA repair pathways and promote error-free DNA repair, said Nussenzweig.
The study also suggests that BRCA1-deficient tumors may become resistant to chemotherapy by acquiring additional mutations in certain DNA repair proteins, but that such resistance may one day be overcome by drugs developed to affect pathway choice, according the researchers.
NIH investigators from the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases also participated in the study, as well as colleagues from Beckman Research Institute of City of Hope, Duarte, Calif.; Rockefeller University, New York City; and the Spanish National Cancer Research Centre, Madrid, Spain.
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Reference: Nussenzweig A, et al. 53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks. Cell, April 16, 2010. DOI 10.1016/j.cell.2010.03.012.