Journal
CELL CYCLE
Volume 3, Issue 12, Pages 1587-1596Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.3.12.1290
Keywords
p63; ubiquitin; SUMO-1; SHFM; split-hand/foot malformation; RUNX2; MINT
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Funding
- NIAID NIH HHS [R01-AI47224] Funding Source: Medline
- NIDCR NIH HHS [R01-DE13561, DE-015834] Funding Source: Medline
- DS NIH HHS [DS-00276-20S1] Funding Source: Medline
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p63 mutations have been identified in several developmental abnormalities, including split-hand/foot malformation (SHFM). In this study, we demonstrate that the C-terminal domain of p63alpha associates with the E2 ubiquitin conjugating enzyme, Ubc9. A p63alpha mutation, Q634X, which naturally occurs in SHFM modulated the interaction of p63alpha with Ubc9 in yeast genetic assay. Furthermore, Ubc9 catalyzed the conjugation of p63alpha with small ubiquitin modifier-1 (SUMO-1), which covalently modified p63alpha in vitro and in vivo at two positions (K549E and K637E), each situated in a SUMO-1 modification consensus site (phiKXD/E). In addition, p63alpha mutations (K549E and K637E) abolished sumoylation of p63alpha, dramatically activated transactivation properties of TAp63alpha, and inhibited the dominant-negative effect of DeltaNp63alpha. These p63alpha mutations also affected the transcriptional regulation of gene targets involved in bone and tooth development (e.g., RUNX2 and MINT) and therefore might contribute to the molecular mechanisms underlying the SHFM phenotype.
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