Funded by 2017 BRCA Fund-A-Need
Nearly 1 million individuals in the United States have inherited mutations in the BRCA1 or BRCA2 cancer susceptibility genes and have a very high risk for several cancers, including breast and ovarian cancer in women. Although clinical screening in individuals with known genetic risk can help identify cancers early when they are potentially more curable, this approach is imperfect. Therefore, there is an urgent need to identify ways to better detect and treat cancers in this high risk population. Like most cancers, those that arise in BRCA1/2 mutation carriers have an unstable genome. Many types of genomic instability are initiated by DNA breaks, particularly in BRCA1/2 carriers, as these genes are normally involved in DNA repair. Understanding how DNA breaks arise and are repaired is thus critical for understanding how cancer arises, and for developing therapies that specifically kill cancer cells or prevent their development. Our work indicates that when genomic DNA is transcribed into RNA, the RNA and DNA may get tangled, creating RNA-DNA hybrid molecules, or R-loops, that cause the DNA to be broken. BRCA1 and BRCA2 proteins help prevent R-loop formation. This raises the possibility that BRCA1 and BRCA2 prevent breast cancer development by regulating the formation of R-loops. In this proposal, we will explore what BRCA1 and BRCA2 do at R-loops, determine where R-loops form in cells without these genes and explore the possibility of using RNA-DNA hybrids as early, sensitive markers of cancer to improve detection and treatment.