title: Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation.
abstract: c-Jun, the major component of the AP-1 transcription factor complex, has important functions in cellular proliferation and oncogenic transformation. The RING domain-containing protein RACO-1 functions as a c-Jun coactivator that molecularly links growth factor signalling to AP-1 transactivation. Here we demonstrate that RACO-1 is present as a nuclear dimer and that c-Jun specifically interacts with dimeric RACO-1. Moreover, RACO-1 is identified as a substrate of the arginine methyltransferase PRMT1, which methylates RACO-1 on two arginine residues. Arginine methylation of RACO-1 promotes a conformational change that stabilises RACO-1 by facilitating K63-linked ubiquitin chain formation, and enables RACO-1 dimerisation and c-Jun interaction. Abrogation of PRMT1 function impairs AP-1 activity and results in decreased expression of a large percentage of c-Jun target genes. These results demonstrate that arginine methylation of RACO-1 is required for efficient transcriptional activation by c-Jun/AP-1 and thus identify PRMT1 as an important regulator of c-Jun/AP-1 function.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors.forename: Clare C
authors.initials: CC
authors.lastname: Davies
authors.forename: Atanu
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Markus E
authors.initials: ME
authors.lastname: Diefenbacher
authors.forename: Mark
authors.initials: M
authors.lastname: Skehel
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C582733:RNF187 protein, human; D044767:Ubiquitin-Protein Ligases