Filling in the gaps in PARP inhibitor-induced synthetic lethality

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...

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Published in:Molecular & cellular oncology 2021, Vol.8 (6), p.2010512-2010512
Main Authors: Paes Dias, Mariana, Jonkers, Jos
Format: Article
Language:English
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BRCA1/2
drug resistance
PARP inhibitors
ssDNA gaps
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description 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.
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subjects BRCA1/2
drug resistance
PARP inhibitors
ssDNA gaps
title Filling in the gaps in PARP inhibitor-induced synthetic lethality
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