The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment.

Szilvia Juhász,Dóra Spekhardt,Tamás Schauer,Catherine Chapuis,Gyula Timinszky,Sébastien Huet,Hasan Mamar,Siham Zentout,Rebecca Smith

doi:10.1126/sciadv.abb8626

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)-a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme-as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

Highlights

Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor important for maintaining genomic integrity
To study the effect of ALC1 deficiency in combination with PARP inhibitors (PARPis) on homologous recombination (HR) and nonhomologous end-joining (NHEJ), we studied the recruitment of Ku70, an actor of NHEJ, as well as Mre11, Rad51, and phosphorylated replication protein A, which are specific to HR, to sites of DNA damage induced by micropore UV irradiation
These findings show that ALC1 deficiency does not display the classical BRCAness signature and that the sensitivity of ALC1KO cells to PARPi arises from defects at the very early stage of the DNA damage response, before the pathway choice between HR and NHEJ

Summary

Introduction

Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor important for maintaining genomic integrity. PARP inhibitors (PARPis) were shown to be toxic for cells deficient in homologous recombination (HR) repair factors BRCA1 (Breast cancer type 1 susceptibility protein) and BRCA2 (Breast cancer type 2 susceptibility protein) even in the absence of exogenous DNA damage, a phenom enon with great therapeutic potential because of the high prevalence of BRCA deficiency in tumor cells [6,7,8]. The observation that the synthetic lethality between BRCA deficiency and PARPi treatment is abrogated by the loss of PARP1 revealed that the inhibited DNA-bound PARP1 is the toxic product—the phenomenon called PARP trapping—rather than deficient DNA damage signaling in the absence of PARylation [4]

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