Journal Article

SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination

Yanling Zhao, Dorothy, Zhong, Guoqing, Blencowe, Benjamin J., Moffat, Jason, Braunschweig, Ulrich, Li, Weiguo, Vedadi, Masoud, Liu, Ke, Min, Jinrong, Ni, Zuyao, Gish, Gerald, Pawson, Tony J., Schmitges, Frank W., Greenblatt, Jack F., Li, Yue

2016

Overview

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. Symmetric dimethylation of the human RNA polymerase II C-terminal domain residue R1810 by the protein arginine methyltransferase 5 (PRMT5) directly recruits the protein survival of motor neuron (SMN) and indirectly recruits the helicase senataxin to resolve R-loops and promote transcription termination. Control of transcription termination The repeating sequence of the C-terminal domain of RNA polymerase II is a favoured target of many modification enzymes. In this study, Jack Greenblatt and colleagues identify and characterize a symmetrical dimethylation modification of an arginine residue, R1810, in the the C-terminal domain. The R1810me2s modification is made by PRMT5, which interacts with SMN (survival of motor neuron) protein, and indirectly with senataxin proteins; mutations in each of these proteins are found in neurodegenerative diseases. The authors propose that the R1810me2s modification of RNA Pol II, together with the activity of SMN and senataxin, is part of a pathway for resolution of transcription-associated R-loops that, if absent, affects gene expression by disrupting transcription termination.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/458/1648 / 631/337/572 / 631/337/572/2102 / 631/45/2783 / Analysis / Arginine / Arginine - metabolism / Cell Line / DNA Damage / Gene expression / Humanities and Social Sciences / Humans / Hybrids / Immunoglobulins / Influence / Methylation / multidisciplinary / Neurodegenerative Diseases - genetics / Peptides / Phosphorylation / Protein Binding / Protein Structure, Tertiary / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - metabolism / Proteins / RNA Helicases - genetics / RNA Helicases - metabolism / RNA polymerase / RNA Polymerase II - chemistry / RNA Polymerase II - metabolism / RNA polymerases / Science / Survival of Motor Neuron 1 Protein - genetics / Survival of Motor Neuron 1 Protein - metabolism / Transcription Elongation, Genetic / Transcription Termination, Genetic