Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

TLDR

PARP3 is a newly characterized PARP family member that catalyzes ADP‑ribosylation, shares structural similarity with PARP1/2, and can synthesize poly(ADP‑ribose), yet its in vivo cellular functions remain largely unknown. The authors combined biochemical assays with loss‑of‑function human and mouse models to characterize PARP3 as a novel contributor to genome integrity and mitotic progression. PARP3 participates in double‑strand break repair, stabilizes the mitotic spindle and telomere integrity through interactions with NuMA and tankyrase‑1, and these dual roles suggest it as a promising target for cancer therapy.

Abstract

The ADP ribosyl transferase [poly(ADP-ribose) polymerase] ARTD3(PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to double-strand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy.