Loading of PAX3 to Mitotic Chromosomes Is Mediated by Arginine Methylation and Associated with Waardenburg Syndrome.

Abstract

PAX3 is a transcription factor critical to gene regulation in mammalian development. Mutations in PAX3 are associated with Waardenburg syndrome (WS), but the mechanism of how mutant PAX3 proteins cause WS remains unclear. Here, we found that PAX3 loads on mitotic chromosomes using its homeodomain. PAX3 WS mutants with mutations in homeodomain lose the ability to bind mitotic chromosomes. Moreover, loading of PAX3 on mitotic chromosomes requires arginine methylation, which is regulated by methyltransferase PRMT5 and demethylase JMJD6. Mutant PAX3 proteins that lose mitotic chromosome localization block cell proliferation and normal development of zebrafish. These results reveal the molecular mechanism of PAX3s loading on mitotic chromosomes and the importance of this localization pattern in normal development. Our findings suggest that PAX3 WS mutants interfere with the normal functions of PAX3 in a dominant negative manner, which is important to the understanding of the pathogenesis of Waardenburg syndrome.

• Authors: Tsu-Fang Wu, Ya-Li Yao, I-Lu Lai, Chien-Chen Lai, Pei-Lun Lin, Wen-Ming Yang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 33 Pg. 20556-64 (Aug 14 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26149688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• PAX3 Transcription Factor
• PAX3 protein, human
• Paired Box Transcription Factors
• Arginine
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Animals
• Arginine (metabolism)
• Chromosomes, Human
• HEK293 Cells
• Humans
• Larva (metabolism)
• Methylation
• Mitosis (genetics)
• PAX3 Transcription Factor
• Paired Box Transcription Factors (genetics)
• Protein-Arginine N-Methyltransferases (metabolism)
• Waardenburg Syndrome (genetics)
• Zebrafish (growth & development)