First Author | Billing D | Year | 2018 |
Journal | Mol Cell | Volume | 72 |
Issue | 1 | Pages | 127-139.e8 |
PubMed ID | 30244837 | Mgi Jnum | J:269011 |
Mgi Id | MGI:6270057 | Doi | 10.1016/j.molcel.2018.08.016 |
Citation | Billing D, et al. (2018) The BRCT Domains of the BRCA1 and BARD1 Tumor Suppressors Differentially Regulate Homology-Directed Repair and Stalled Fork Protection. Mol Cell 72(1):127-139.e8 |
abstractText | The BRCA1 tumor suppressor 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 phosphate-binding BRCT domain. Here, we compare mice with mutations that ablate BRCT phospho-recognition by Bard1 (Bard1(S563F) and Bard1(K607A)) or Brca1 (Brca1(S1598F)). Brca1(S1598F) abrogates both HDR and SFP, suggesting that both pathways are likely impaired in most BRCA1 mutant tumors. Although not affecting HDR, the Bard1 mutations ablate poly(ADP-ribose)-dependent recruitment of BRCA1/BARD1 to stalled replication forks, resulting in fork degradation and chromosome instability. Nonetheless, Bard1(S563F/S563F) and Bard1(K607A/K607A) mice, unlike Brca1(S1598F/S1598F) mice, are not tumor prone, indicating that HDR alone is sufficient to suppress tumor formation in the absence of SFP. Nevertheless, because SFP, unlike HDR, is also impaired in heterozygous Brca1/Bard1 mutant cells, SFP and HDR may contribute to distinct stages of tumorigenesis in BRCA1/BARD1 mutation carriers. |