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

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

one for p63 having an N-terminal transactivation domain (TA) and the other for p63 lacking TA domain (N). In addition, both TA and N transcripts are differentially spliced at their 3 ends to generate the p63 proteins with unique Ctermini, termed , , , , and  (Melino, 2011) . Similar to p53, TAp63 isotypes can activate transcription from p53responsive genes, which induce cell cycle arrest and apoptosis, thus also functioning as tumor suppressors (Flores et al., 2002; Suh et al., 2006) . Of the p63 isotypes, Np63 has the transactivation inhibitory domain (TI) but lacks the TA domain and therefore can dominant-negatively suppress transcriptional activation of the p53 family member by binding to their TA domains (Guo et al., 2009; Sayan et al., 2007; Yang et al., 1998) , contributing to its anti-apoptotic, mitogenic, and tumorigenic Fig. 1 . Positive feedback regulation of p53 transactivity by ISG15 modification. When cells are insulted by DNA-damaging agents, p53 is phosphorylated and acetylated, such as by Chk1 and p300, respectively, resulting in its dissociation from MDM2 and stabilization. The stabilized p53 is then conjugated by ISG15 and this modification increases phosphorylation (pink circle: P) and acetylation (blue circle: A) of p53 and in turn in its ability to bind p53RE for the expression of ISG15, its conjugating system (E1-3), and other targets, including p21 and BAX, as well as itself. This increased expression of ISG15 and E1-3 ISG15 molecules for reloading replicative DNA polymerases and thereby for resuming normal DNA replication.