ZNF432 stimulates PARylation and inhibits DNA resection to balance PARPi sensitivity and resistance
Julia O’Sullivan, Charu Kothari, Marie‐Christine Caron, Jean‐Philippe Gagné, Zhigang Jin, Louis Nonfoux, Adèle Beneyton, Yan Coulombe, Mélissa Thomas, Nurgül Atalay, X. Wei Meng, Larissa Milano, Dominique Jean, François‐Michel Boisvert, Scott H. Kaufmann, Michael J. Hendzel, Jean‐Yves Masson, Guy G. Poirier
Abstract
Zinc finger (ZNF) motifs are some of the most frequently occurring domains in the human genome. It was only recently that ZNF proteins emerged as key regulators of genome integrity in mammalian cells. In this study, we report a new role for the Krüppel-type ZNF-containing protein ZNF432 as a novel poly(ADP-ribose) (PAR) reader that regulates the DNA damage response. We show that ZNF432 is recruited to DNA lesions via DNA- and PAR-dependent mechanisms. Remarkably, ZNF432 stimulates PARP-1 activity in vitro and in cellulo. Knockdown of ZNF432 inhibits phospho-DNA-PKcs and increases RAD51 foci formation following irradiation. Moreover, purified ZNF432 preferentially binds single-stranded DNA and impairs EXO1-mediated DNA resection. Consequently, the loss of ZNF432 in a cellular system leads to resistance to PARP inhibitors while its overexpression results in sensitivity. Taken together, our results support the emerging concept that ZNF-containing proteins can modulate PARylation, which can be embodied by the pivotal role of ZNF432 to finely balance the outcome of PARPi response by regulating homologous recombination.