PARP10 Mediates Mono-ADP-Ribosylation of Aurora-A Regulating G2/M Transition of the Cell Cycle

SIMPLE SUMMARY: Mono-ADP-ribosylating PARP enzymes are involved in the regulation of several cellular pathways, including cell cycle. The mono-ADP-ribosyltransferase PARP10 is frequently amplified in different tumor types, and has been shown to promote in vitro cellular proliferation and in vivo tumoral growth. The aim of our study was to investigate the role of PARP10 in the regulation of G2/M transition. We found that PARP10 is involved in the mono-ADP-ribosylation of Aurora-A, an important mitotic kinase, during the G2/M transition. Moreover, PARP10-catalyzed modification enhances the kinase activity of Aurora-A. Consistently, the depletion of PARP10 affects the timely recruitment of Aurora-A on centrosomes and mitotic spindle, causing a delay in mitotic entry. Our discovery provides novel details in the cellular functions exerted by PARP10. ABSTRACT: Intracellular mono-ADP-ribosyltransferases (mono-ARTs) catalyze the covalent attachment of a single ADP-ribose molecule to protein substrates, thus regulating their functions. PARP10 is a soluble mono-ART involved in the modulation of intracellular signaling, metabolism and apoptosis. PARP10 also participates in the regulation of the G1- and S-phase of the cell cycle. However, the role of this enzyme in G2/M progression is not defined. In this study, we found that genetic ablation, protein depletion and pharmacological inhibition of PARP10 cause a delay in the G2/M transition of the cell cycle. Moreover, we found that the mitotic kinase Aurora-A, a previously identified PARP10 substrate, is actively mono-ADP-ribosylated (MARylated) during G2/M transition in a PARP10-dependent manner. Notably, we showed that PARP10-mediated MARylation of Aurora-A enhances the activity of the kinase in vitro. Consistent with an impairment in the endogenous activity of Aurora-A, cells lacking PARP10 show a decreased localization of the kinase on the centrosomes and mitotic spindle during G2/M progression. Taken together, our data provide the first evidence of a direct role played by PARP10 in the progression of G2 and mitosis, an event that is strictly correlated to the endogenous MARylation of Aurora-A, thus proposing a novel mechanism for the modulation of Aurora-A kinase activity.