Abstract
Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in . Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, . Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in . Brca1-deficient cells; however deletion of either . Ku or . 53BP1 exacerbates genomic instability in cells lacking . FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.
Original language | American English |
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Pages (from-to) | 125-135 |
Number of pages | 11 |
Journal | Molecular cell |
Volume | 46 |
Issue number | 2 |
DOIs | |
State | Published - Apr 27 2012 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology