title: 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.affiliation: From the Department of Life Sciences, Department of Biotechnology, Hung Kuang University, Taichung 43302, Taiwan.
authors.forename: Tsu-Fang
authors.initials: TF
authors.lastname: Wu
authors.affiliation: Department of Biotechnology, Asia University, Taichung 41354, Taiwan, and yyao@asia.edu.tw.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Yao
authors.affiliation: the Institute of Molecular Biology, and.
authors.forename: I-Lu
authors.initials: IL
authors.lastname: Lai
authors.affiliation: the Institute of Molecular Biology, and.
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Bachelor Program of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Lin
authors.affiliation: the Institute of Molecular Biology, and yangwm@nchu.edu.tw.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002877:Chromosomes, Human; D057809:HEK293 Cells; D006801:Humans; D007814:Larva / Q000378:metabolism; D008745:Methylation; D008938:Mitosis / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D014849:Waardenburg Syndrome / Q000235:genetics*; D015027:Zebrafish / Q000254:growth & development
chemical_list: D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: PAX3; arginine methylation; chromosomes; homeobox; homeodomain; mitosis; mitotic chromosome; mutant; protein arginine N-methyltransferase 5 (PRMT5); transcription factor