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Publication Detail

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

Authors: Clements, Kristen E; Schleicher, Emily M; Thakar, Tanay; Hale, Anastasia; Dhoonmoon, Ashna; Tolman, Nathanial J; Sharma, Anchal; Liang, Xinwen; Imamura Kawasawa, Yuka; Nicolae, Claudia M; Wang, Hong-Gang; De, Subhajyoti; Moldovan, George-Lucian

Published In Nat Commun, (2020 11 30)

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.

PubMed ID: 33257658 Exiting the NIEHS site

MeSH Terms: BRCA2 Protein/genetics; BRCA2 Protein/metabolism; Biomarkers; Clustered Regularly Interspaced Short Palindromic Repeats*; DNA Damage; DNA Repair; Gene Knockout Techniques; HeLa Cells; Homologous Recombination/drug effects; Humans; Lysine Acetyltransferase 5/metabolism; Mad2 Proteins/metabolism; Poly(ADP-ribose) Polymerase Inhibitors/isolation & purification*; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology*; Poly(ADP-ribose) Polymerases/drug effects*; Rad51 Recombinase/genetics; Rad51 Recombinase/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Tumor Suppressor p53-Binding Protein 1; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism

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