Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens

Kristen E. Clements, Emily M. Schleicher, Tanay Thakar, Anastasia Hale, Ashna Dhoonmoon, Nathanial J. Tolman, Anchal Sharma, Xinwen Liang, Yuka Imamura Kawasawa, Claudia M. Nicolae, Hong-Gang Wang, Subhajyoti De and George-Lucian Moldovan ()
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Kristen E. Clements: The Pennsylvania State University College of Medicine
Emily M. Schleicher: The Pennsylvania State University College of Medicine
Tanay Thakar: The Pennsylvania State University College of Medicine
Anastasia Hale: The Pennsylvania State University College of Medicine
Ashna Dhoonmoon: The Pennsylvania State University College of Medicine
Nathanial J. Tolman: The Pennsylvania State University College of Medicine
Anchal Sharma: Rutgers the State University of New Jersey
Xinwen Liang: The Pennsylvania State University College of Medicine
Yuka Imamura Kawasawa: The Pennsylvania State University College of Medicine
Claudia M. Nicolae: The Pennsylvania State University College of Medicine
Hong-Gang Wang: The Pennsylvania State University College of Medicine
Subhajyoti De: Rutgers the State University of New Jersey
George-Lucian Moldovan: The Pennsylvania State University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells.

Date: 2020
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DOI: 10.1038/s41467-020-19961-w

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