Project Summary Approximately 57,000 American women will succumb to triple negative breast cancer (TNBC) in 2020. While only a subset of all breast cancers, they are highly aggressive and offer the worst prognosis. Recurrence rate is high, especially in African-American women, and to date no targeted therapies are available. There is thus an urgent need to develop new treatment options. Despite large-scale genome sequencing efforts, known breast cancer loci still explain only one- third of breast cancer risk. It is therefore imperative to identify additional breast cancer susceptibility genes and elucidate their mechanisms of action to enable the development of comprehensive cancer risk assessment and targeted therapeutics. We recent discovered that Claspin, PCNA and DONSON, components of the DNA replication machinery, specifically interact with the telomere binding protein TRF2 at dysfunctional telomeres in BRCA1 null TNBCs. This novel discovery provides new insights into mechanisms of how the replisome complex confers a survival advantage to BRCA1 null TNBCs. Understanding how the replisome protects newly replicated telomeres in BRCA1 null TNBCs will be highly valuable for the generation of new therapeutics against this deadly disease.