DNA end-resection is stimulated by an interaction between BRCA1 exon 11 and TOPBP1

Abstract

Abstract Approximately 60% of the tumour suppressor protein BRCA1 is encoded by a single exon. Many tumours carry mutations in this exon, often resulting in exon skipping and thus a protein of a severely reduced size. Although none of the well-described protein domains of BRCA1 are encoded by this exon 11, the isoform lacking this part shows a hypomorphic activity in homologous recombination. To better understand the function of this large exon, we performed proteomic analyses to identify interaction partners via this part of the protein. Here, we report a DNA damage- and phospho-dependent interaction of TOPBP1 with the protein region of BRCA1 encoded by exon 11. Mechanistically, this interaction is required for BRCA1’s role in end-resection during homologous recombination. In contrast, the interaction is not required for TOPBP1’s role in ATR activation. Our data provide novel mechanistic insight into the function of this poorly characterized part of the BRCA1 protein.