Replication fork protection reduces chemosensitivity in BRCA-deficient cells without restoring HR.
Major finding: Replication fork protection reduces chemosensitivity in BRCA-deficient cells without restoring HR.
Mechanism: PTIP recruits the MRE11 nuclease to stalled replication forks to promote nascent DNA degradation.
Impact: Drug resistance in BRCA-deficient cells can result from the prevention of nascent DNA degradation.
BRCA1 and BRCA2 are involved in DNA double-strand break (DSB) repair, and BRCA1/2-deficient cells are hypersensitive to DNA damage due to their reduced ability to repair DSBs by homologous recombination (HR). BRCA-deficient cells are initially sensitive to DNA-damaging agents including cisplatin and PARP inhibitors, but often acquire resistance through HR restoration. As BRCA1 and BRCA2 have DSB-independent functions during replicative stress, Chaudhuri, Callen, and colleagues sought to identify additional mechanisms of DNA damage resistance in BRCA-deficient cells. Inactivation of Brca1 or Brca2 in B lymphocytes resulted in replication fork degradation in response to hydroxyurea-induced replication fork stalling. Replication fork degradation is dependent on MRE11 exonuclease activity, and the MLL3/4 complex protein PTIP can inhibit MRE11-dependent DSB resection, thereby preventing BRCA1-dependent HR, but it is not known if PTIP plays a role in replication fork stability. Depletion of PTIP prevented replication fork degradation in response to hydroxyurea. Compared with Brca1 or Brca2 depletion alone, double depletion of Brca1/2 and Ptip increased cell viability and reduced chromosomal aberrations, altogether indicating that PTIP can function at stalled replication forks independent of the DSBs. Further, Ptip loss promoted replication fork progression and prevented the delayed restart in Brca2−/− cells, which was associated with reduced replication fork degradation. PTIP accumulated at stalled replication forks and recruited MRE11. The replication fork stability induced by PTIP loss conferred chemoresistance, likely by enhancing genome stability in response to chemotherapeutics. Data from The Cancer Genome Atlas revealed that in patients with BRCA2-mutant tumors treated with platinum-based chemotherapy, high PTIP expression was associated with increased progression-free survival, indicating that PTIP expression might be a potential biomarker for chemoresistance. These findings suggest that in BRCA-deficient tumors, replication fork protection can prevent genome instability and lead to chemoresistance independent of HR restoration.
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