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Altered Sumoylation of p63α Contributes to the Split-Hand/Foot Malformation Phenotype

Yi-Ping Huang, Guojun Wu, Zhongmin Guo, Motonobu Osada,Tanya Fomenkov, Hannah Lui Park, Barry Trink, DavidSidransky, Alexey Fomenkov and Edward A. Ratovitski

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p63 mutations have been identified in several developmental abnormalities, including splithand/ foot malformation (SHFM). In this study, we demonstrate that the C-terminal domain of p63α associates with the E2 ubiquitin conjugating enzyme, Ubc9. A p63α mutation, Q634X, which naturally occurs in SHFM modulated the interaction of p63α with Ubc9 in yeast genetic assay. Furthermore, Ubc9 catalyzed the conjugation of p63α with small ubiquitin modifier-1 (SUMO-1), which covalently modified p63α in vitro and in vivo at two positions (K549E and K637E), each situated in a SUMO-1 modification consensus site (?KXD/E). In addition, p63? mutations (K549E and K637E) abolished sumoylation of p63α, dramatically activated transactivation properties of TAp63α, and inhibited the dominant-negative effect of ΔNp63α. These p63? 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.

Authors

Yi-Ping Huang

Guojun Wu

Zhongmin Guo

Motonobu Osada

Tanya Fomenkov

Hannah Lui Park

Barry Trink

DavidSidransky

Alexey Fomenkov

Edward A. Ratovitski

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.