title: SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination.
abstract: The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAP II) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. Here we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires protein arginine methyltransferase 5 (PRMT5) and recruits the Tudor domain of the survival of motor neuron (SMN, also known as GEMIN1) protein, which is mutated in spinal muscular atrophy. SMN interacts with senataxin, which is sometimes mutated in ataxia oculomotor apraxia type 2 and amyotrophic lateral sclerosis. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, we propose that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. Defects in this pathway can influence transcription termination and may contribute to neurodegenerative disorders.
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Dorothy Yanling
authors.initials: DY
authors.lastname: Zhao
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Gish
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Braunschweig
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Zuyao
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Schmitges
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Li
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Pawson
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Greenblatt
mesh_terms: D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases; D006801:Humans; D008745:Methylation; D064251:Multifunctional Enzymes; D019636:Neurodegenerative Diseases / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000737:chemistry* / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D061805:Transcription Elongation, Genetic; D061806:Transcription Termination, Genetic
chemical_list: D064251:Multifunctional Enzymes; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D012319:RNA Polymerase II; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases