DNA polymerase θ (Polθ) inhibits homologous recombination (HR) and promotes alternative NHEJ.

  • Major finding: DNA polymerase θ (PoLθ) inhibits homologous recombination (HR) and promotes alternative NHEJ.

  • Clinical relevance: HR-deficient cancer cells depend on PoLθ-mediated alternative NHEJ repair for survival.

  • Impact: DNA PoLθ may serve as a potential biomarker and therapeutic target in HR-deficient cancers.

Defects in homologous recombination (HR) repair lead to genomic instability in specific types of tumors such as breast and epithelial ovarian cancers, and result in dependence on alternative PARP-driven and error-prone DNA repair pathways. Ceccaldi and colleagues found that DNA polymerase theta (POLθ, encoded by POLQ) expression increased with epithelial ovarian cancer grade and suppressed HR by binding the RAD51 recombinase and inhibiting its assembly at single-stranded DNA. POLθ ATPase activity and RAD51 binding were stimulated by replicative stress, and suppression of POLθ sensitized cells to genotoxic stress and DNA damage, resulting in reduced DNA replication fork dynamics and impaired cell-cycle progression and suggesting a role for POLθ at stalled replication forks. Importantly, POLθ expression was increased in HR-deficient ovarian cancer cells, predicted patient response to platinum chemotherapy, and conferred hypersensitivity to HR deficiency, indicative of synthetic lethality. Consistent with these findings, Mateos-Gomez and colleagues identified POLθ as a key modulator of HR and alternative nonhomologous end-joining (alt-NHEJ) DNA repair using genetically engineered mouse models that allow for differentiation between classical and alt-NHEJ. Suppression of POLθ inhibited the generation of telomere fusions and chromosomal translocations formed by alt-NHEJ, but not classical NHEJ. POLθ was recruited to DNA double-strand breaks in a PARP1-dependent manner, and suppression of POLθ led to decreased alt-NHEJ and a concomitant increase in HR via enhanced RAD51 accumulation. Moreover, suppression of POLθ in HR-deficient BRCA-mutant cells led to increased chromosomal aberrations and reduced cell survival, further supporting the notion that HR-deficient tumors are dependent on POLθ to maintain genomic stability. Together, these studies highlight a previously unrecognized role for POLθ in regulating the balance between HR and alt-NHEJ repair and provide a rationale for the therapeutic targeting of POLθ in HR-deficient cancers.

Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 2015;518:258–62.

Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 2015;518:254–7.

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