Poly(ADP‐ribosyl)ation of OVOL2 regulates aneuploidy and cell death in cancer cells

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-fingers domain. 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. Support or Funding Information This work was supported in part by Grants R-154-000-637-511 from the Ministry of Education (MOE), National Medical Research Council (NMRC), Singapore to Y.C.L. Schematic diagram illustrating the role of PARylated OVOL2 in maintaining the stability of Cyclin E. Accumulated Cyclin E2 leads to aberrant amplification of centromeres and chromosome instability, resulting in tumor cell death. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.