Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress

Jeon, Young Joo; Park, Jong Ho; Chung, Chin Ha

HERC5 lacks p53RE, consistently with the finding that the ligase is not induced under DNA-damaging conditions. Intriguingly, ISGylation of p53 promotes its transcriptional activity and in turn in the expression of its downstream target genes, including CDKN1, MDM2, BAX, and ISG15, as well as of its own gene. This increase of the p53 activity is mediated by the ability of ISG15-conjugated p53 to promote its phosphorylation and acetylation and thereby to increase its affinity toward p53RE. Furthermore, p53 ISGylation suppresses cell growth and tumor development in vivo. Knockdown of ISG15 or any of the ISG15-conjugating system or Lys-to-Arg mutations of the ISG15 acceptor sites in p53 strongly attenuates DNA damage-induced p53 activity and in turn its tumor suppressive function (Park et al., 2016) . Thus, cells appear to operate a novel feedback circuit between p53 and the ISG15-conjugating system for positive control of p53 tumor suppressive function under genotoxic stress conditions.