Mutations in RNASEH2B impair ribonucleotide excision repair to confer PARP inhibitor sensitivity.

  • Major finding: Mutations in RNASEH2B impair ribonucleotide excision repair to confer PARP inhibitor sensitivity.

  • Mechanism: Genome-embedded ribonucleotides provide a substrate for TOP1 cleavage to promote PARP trapping.

  • Impact: Patients with RNASEH2B-deficient tumors may benefit from treatment with PARP inhibitors.

Tumors with homologous recombination deficiencies are generally sensitive to PARP inhibitors including olaparib and talazoparib. PARP inhibitor efficacy depends on PARP trapping, the formation of noncovalent interactions between inhibited PARP1 and DNA lesions, but the cellular consequences of PARP trapping remain unclear. Zimmermann, Murina, and colleagues performed CRISPR dropout screens in olaparib-treated cells to identify genes that promote resistance to PARP inhibition. Overall, 73 genes were identified that, when mutated, increased sensitivity to PARP inhibitors. Many of these were genes involved in homologous recombination or other DNA damage response and repair processes. However, mutations in the three genes encoding the ribonuclease (RNase) H2 complex (RNASEH2A, RNASEH2B, and RNASEH2C) also sensitized cells to PARP inhibition. RNase H2 can cleave single ribonucleotides misincorporated into DNA, and RNase H2 mutations impaired ribonucleotide excision repair to induce PARP inhibitor sensitivity. In RNASEH2A-deficient cells, PARP inhibition resulted in PARP1-dependent arrest in S phase that was associated with increased γ-H2AX foci that remained after drug removal, suggesting that unresolved DNA lesions induced by PARP trapping resulted in apoptosis. Cells with RNase H2 mutations and impaired ribonucleotide excision repair have abundant embedded ribonucleotides throughout the genome, which provides a substrate for topoisomerase I (TOP1) cleavage, resulting in DNA lesions that engage PARP1. Analysis of patient samples revealed that RNASEH2B deletions occurred in 43% of patients with CLL, and 34% of castration-resistant prostate cancers exhibited collateral loss of RNASEH2B and RB1. These deletions were associated with increased sensitivity to talazoparib in vitro and in vivo. Collectively, these findings suggest that genomic ribonucleotides may underlie PARP-trapping DNA lesions and suggest the potential for treating patients with RNASEH2B deletions with PARP inhibitors.

Zimmermann M, Murina O, Reijns MA, Agathanggelou A, Challis R, Tarnauskaitė Ž, et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 2018;559:285–9.

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