title: TLS and PRMT1 synergistically coactivate transcription at the survivin promoter through TLS arginine methylation.
abstract: TLS (Translocated in LipoSarcoma), also termed FUS, is a multifunctional protein implicated in diverse cellular events such as maintaining genome integrity and regulating gene expression. We have focused on the role of TLS as a coregulator in transcriptional regulation. In the process of investigating TLS-binding proteins, we found that PRMT1 (protein arginine methyltransferase 1) was in complex with TLS. We analyzed the methylation status of endogenous TLS and demonstrated that TLS was arginine-methylated by PRMT1. Using mass spectrometry, we identified that four arginine residues within TLS (R216, R218, R242 and R394) were consistently dimethylated. We performed luciferase reporter assays to assess the functional consequence of TLS arginine methylation in transcriptional regulation and, interestingly, observed that TLS and PRMT1 synergistically coactivated transcription at the survivin promoter. Further analysis using a catalytic-dead PRMT1 or methylation inhibitor both showed that the synergistic transcriptional activation was mediated by TLS arginine-methylation. These results revealed a cooperative role of TLS and PRMT1 in transcriptional regulation.
authors.affiliation: Division of Gene Structure and Function, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama-ken 350-1241, Japan.
authors.forename: Kun
authors.initials: K
authors.lastname: Du
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Akio
authors.initials: A
authors.lastname: Matsushita
authors.forename: Riki
authors.initials: R
authors.lastname: Kurokawa
mesh_terms: D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D013058:Mass Spectrometry; D008745:Methylation / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; D000077022:Survivin; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases