DECIPHERING POLY(ADP-RIBOSYL)ATION-DEPENDENT FUNCTION OF OVOL2 IN TUMOR SUPPRESSION

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification by which poly ADP-ribose (PAR) polymers are covalently added to proteins through a PAR polymerase (PARP). Here, we identify that the transcriptional regulator, OVOL2, is a novel substrate for PARP1 and can be PARylated at residues Lysine 145, Lysine 176, and Lysine 212, within the C2H2 zinc finger domains. PARylated OVOL2 acts as a transcriptional suppressor directly inhibiting downstream expression of the E3 ligase, Skp2, which promotes ubiquitin-dependent degradation of Cyclin E, thus leading to an accumulation of Cyclin E during cell cycle progression. As a result, overexpression of OVOL2, but not the non-PARylated OVOL2-3K/A mutant, induces aberrant centrosome amplification and chromosome instability, resulting in aneuploidy and subsequent cell death. Overexpression of PARylated OVOL2 in vivo resulted in a significant reduction in tumor progression, supporting the function of OVOL2 as a tumor suppressor, which is highly regulated by PARylation.