The BRCA1 tumour suppressor is understood to function in the error-free repair of DNA lesions by homologous recombination (HR), yet its actual role in this process is ill-defined. Based on recent experimental observations, I propose what may be the critical role for BRCA1 in maintaining genome stability: antagonising the protein 53BP1 during DNA double-strand break (DSB) repair. Upon BRCA1-deficiency, I predict that DSBs normally repaired by HR during the replicative cell cycle phases, are inapp ropriately repaired by 53BP1-dependent error-prone non-homologous end-joining (NHEJ). Such aberrant repair likely produces the chromosomal rearrangements associated with malignant transformation in BRCA1-deficient cells. My proposed experiments have three core aims: 1. Define the antagonistic role of BRCA1 in inhibiting the repair of DSBs by 53BP1-dependent NHEJ. 2. Establish the molecular determinants of 53BP1-dependent NHEJ. 3. Elucidate the involvement of Rif1 in the antagonism of 53BP1 -dependent DSB repair by BRCA1. I anticipate that the proposed study will provide insights into the elusive functions of BRCA1 in maintaining genomic integrity, which will enhance our knowledge of its molecular role as a tumour suppressor. This work might also identify new avenues to exploit in the clinic to treat BRCA1-associated hereditary and sporadic cancers potentially associated with 53BP1-misregulation.