Filling in the gaps in PARP inhibitor-induced synthetic lethality

Mariana Paes Dias; Jos Jonkers

doi:10.1080/23723556.2021.2010512

Filling in the gaps in PARP inhibitor-induced synthetic lethality

Mol Cell Oncol. 2021 Dec 6;8(6):2010512. doi: 10.1080/23723556.2021.2010512. eCollection 2021.

Authors

Mariana Paes Dias^{1

2}, Jos Jonkers^{1

2}

Affiliations

¹ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
² Oncode Institute, Amsterdam, The Netherlands.

Abstract

Tumors with loss of breast cancer type 1 susceptibility protein (BRCA1) are homologous recombination (HR) deficient and hypersensitive to poly(ADP-ribose) polymerase inhibitors (PARPi). However, these tumors may restore HR and acquire PARPi resistance via loss of end-protection of DNA double-strand breaks. We found that loss of nuclear DNA ligase III resensitizes HR-restored BRCA1-deficient cells to PARPi by exposing post-replicative single-stranded DNA (ssDNA) gaps. Our work, and that of others, identifies ssDNA gaps as a key determinant of PARPi response.

Keywords: BRCA1/2; PARP inhibitors; drug resistance; ssDNA gaps.

Grants and funding

Our work is supported by grants from the European Union Horizon 2020 research and innovation program (agreement 722729) and Oncode Institute, which is partly financed by the Dutch Cancer Society (KWF).