2018 Theses Doctoral

The BARD1 BRCT Domain in Tumor Suppression and Genome Stability

Billing, David

BRCA1 preserves genome integrity through both homology-directed repair (HDR) and stalled fork protection (SFP). In vivo, BRCA1 exists as a heterodimer with the BARD1 tumor suppressor, and both proteins harbor a C-terminal BRCT domain with a phospho-recognition surface. Most pathogenic lesions of BRCA1 and BARD1 disrupt their respective BRCT domains, and BRCA1 BRCT phospho-recognition is required for its tumor suppression activity. Here we evaluate mice with mutations (Bard1S563F and Bard1K607A) that ablate Bard1 BRCT phospho-recognition. Although not affecting HDR, these mutations impair BRCA1/BARD1 recruitment to stalled replication forks, resulting in stalled fork degradation, chromosomal instability, and sensitivity to PARP inhibitors. However, Bard1S563F/S563F and Bard1K607A/K607A mice are not tumor-prone, indicating that ablation of SFP activity alone is insufficient for spontaneous tumor susceptibility. Nevertheless, since SFP, unlike HDR, is also impaired in Brca1/Bard1 heterozygous-mutant cells, SFP and HDR may contribute to distinct stages of tumor development in BRCA1/BARD1 mutation carriers.