Abstract B056: Modulation of the DNA replication stress response and chemo-response by the mono-ADP-ribosyltransferase PARP14

Abstract

Abstract Genomic instability is a major hallmark of cancer and one of the most common causes is DNA replication stress. Mutations in genes involved in the DNA replication stress response are closely linked to cancer predisposition and progression but this has been exploited clinically. In the advent of personalized medicine, it has become clear that a better understanding of underlying mechanisms is important to advance cancer therapy, especially to address chemoresistance. Here, we identified novel roles for PARP14, a lesser studied member of the PARP family, in regulation of the replication stress response, and subsequently genomic stability and chemo-response. PARP14 is an ADP-ribosyltransferase with multiple roles in transcription, signaling, and DNA repair. To understand the biological functions of PARP14, we first catalogued the genetic components that impact cellular viability upon loss of PARP14 by performing an unbiased, comprehensive, genome-wide CRISPR knockout genetic screen in PARP14-deficient cells. We uncovered the ATR-CHK1 pathway as essential for viability of PARP14-deficient cells and identified regulation of DNA replication dynamics as an important mechanistic contributor to the synthetic lethality observed. Furthermore, we showed that PARP14 plays a central role in stabilization of stalled replication forks which arise due to high replication stress level in BRCA1/2 deficient cells. Mechanistically, we showed that PARP14 mediates stalled replication fork degradation via its interaction with the nuclease MRE11. Moreover, we also identified KU as an essential component of a multi-step mechanism by which the KU-PARP14 axis differentially promotes degradation by the nucleases MRE11 and EXO1. This mechanism restores genomic stability in BRCA-deficient cells and subsequently promotes chemoresistance. Overall, our work provides insights into novel mechanisms by which PARP14 affects the replication stress response and demonstrates that PARP14 can be used as a biomarker for chemo-response. Citation Format: Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan. Modulation of the DNA replication stress response and chemo-response by the mono-ADP-ribosyltransferase PARP14 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B056.