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

• Published in: The Journal of biological chemistry 2015-08, Vol.290 (33), p.20556-20564
• Main Authors: Wu, Tsu-Fang, Yao, Ya-Li, Lai, I-Lu, Lai, Chien-Chen, Lin, Pei-Lun, Yang, Wen-Ming
• Format: Article
• Language: English
• Subjects: Animals; Arginine - metabolism; arginine methylation; chromosomes; Chromosomes, Human; HEK293 Cells; homeobox; homeodomain; Humans; Larva - metabolism; Methylation; mitosis; Mitosis - genetics; mitotic chromosome; Molecular Bases of Disease; mutant; Paired Box Transcription Factors - genetics; PAX3; PAX3 Transcription Factor; protein arginine N-methyltransferase 5 (PRMT5); Protein-Arginine N-Methyltransferases - metabolism; transcription factor; Waardenburg Syndrome - genetics; Zebrafish - growth & development
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.607713

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. Background: Mutations in PAX3 cause Waardenburg syndrome (WS), but the mechanism remains unclear. Results: PAX3 binds mitotic chromosomes using its homeodomain (HD), a process that depends on arginine methylation and is lost in WS. Conclusion: PAX3 with mutations in HD causes WS by failing to load on mitotic chromosomes. Significance: This study pinpoints the molecular defects of a specific group of PAX3 WS mutants.