Roles for SUMO in pre‐mRNA processing

Advanced Review

Patrick K. Nuro‐Gyina, Jeffrey D. Parvin

Published Online: Nov 13 2015

DOI: 10.1002/wrna.1318

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

When the small ubiquitin‐like modifier (SUMO)‐1 protein is localized on the genome, it is found on proteins bound to the promoters of the most highly active genes and on proteins bound to the DNA‐encoding exons. Inhibition of the SUMO‐1 modification leads to reductions in initiation of messenger RNA (mRNA) synthesis and splicing. In this review, we discuss what is known about the SUMOylation of factors involved in transcription initiation, pre‐mRNA processing, and polyadenylation. We suggest a mechanism by which SUMO modifications of factors at the promoters of high‐activity genes trigger the formation of an RNA polymerase II complex that coordinates and integrates the stimulatory signals for each process to catalyze an extremely high level of gene expression. WIREs RNA 2016, 7:105–112. doi: 10.1002/wrna.1318 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing

Model for SUMOylation‐mediated fast‐track transcription and processing of messenger RNA (mRNA). In this depiction, many factors have been left out to emphasize how ‘active’ transcription may differ from ‘fast‐track’ expression. We model that on most RNA polymerase II (RNAPII) templates, transcription occurs by multiple independent protein–protein and protein–template interactions to yield a pre‐mRNA product that is likely processed co‐transcriptionally. We model that the key difference with the fast‐track synthesis is the SUMO modification of multiple factors, including SAFB, splicing factors, and polyadenylation factors, to stimulate the physical interaction of these complexes and coordinate the change from an active level of expression to a significantly higher level of expression, driving mRNA levels for these genes to very high abundances.

[ Normal View | Magnified View ]

References

Saitoh, H, Pu, RT, Dasso, M. SUMO‐1: wrestling with a new ubiquitin‐related modifier. Trends Biochem Sci 1997, 22:374–376.
Shen, Z, Pardington‐Purtymun, PE, Comeaux, JC, Moyzis, RK, Chen, DJ. UBL1, a human ubiquitin‐like protein associating with human RAD51/RAD52 proteins. Genomics 1996, 36:271–279.
Johnson, ES, Blobel, G. Ubc9p is the conjugating enzyme for the ubiquitin‐like protein Smt3p. J Biol Chem 1997, 272:26799–26802.
Dye, BT, Schulman, BA. Structural mechanisms underlying posttranslational modification by ubiquitin‐like proteins. Annu Rev Biophys Biomol Struct 2007, 36:131–150.
Matunis, MJ, Coutavas, E, Blobel, G. A novel ubiquitin‐like modification modulates the partitioning of the Ran‐GTPase‐activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol 1996, 135:1457–1470.
Mahajan, R, Gerace, L, Melchior, F. Molecular characterization of the SUMO‐1 modification of RanGAP1 and its role in nuclear envelope association. J Cell Biol 1998, 140:259–270.
Psakhye, I, Jentsch, S. Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair. Cell 2012, 151:807–820.
Galanty, Y, Belotserkovskaya, R, Coates, J, Polo, S, Miller, KM, Jackson, SP. Mammalian SUMO E3‐ligases PIAS1 and PIAS4 promote responses to DNA double‐strand breaks. Nature 2009, 462:935–939.
Morris, JR, Boutell, C, Keppler, M, Densham, R, Weekes, D, Alamshah, A, Butler, L, Galanty, Y, Pangon, L, Kiuchi, T, et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 2009, 462:886–890.
Potts, PR, Yu, H. Human MMS21/NSE2 is a SUMO ligase required for DNA repair. Mol Cell Biol 2005, 25:7021–7032.
Hu, Y, Parvin, JD. Small ubiquitin‐like modifier (SUMO) isoforms and conjugation‐independent function in DNA double‐strand break repair pathways. J Biol Chem 2014, 289:21289–21295.
Harder, Z, Zunino, R, McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 2004, 14:340–345.
Martin, S, Nishimune, A, Mellor, JR, Henley, JM. SUMOylation regulates kainate‐receptor‐mediated synaptic transmission. Nature 2007, 447:321–325.
Dadke, S, Cotteret, S, Yip, SC, Jaffer, ZM, Haj, F, Ivanov, A, Rauscher, F 3rd, Shuai, K, Ng, T, Neel, BG, et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol 2007, 9:80–85.
Johnson, ES, Blobel, G. Cell cycle‐regulated attachment of the ubiquitin‐related protein SUMO to the yeast septins. J Cell Biol 1999, 147:981–994.
Guo, B, Sharrocks, AD. Extracellular signal‐regulated kinase mitogen‐activated protein kinase signaling initiates a dynamic interplay between sumoylation and ubiquitination to regulate the activity of the transcriptional activator PEA3. Mol Cell Biol 2009, 29:3204–3218.
Ouyang, J, Shi, Y, Valin, A, Xuan, Y, Gill, G. Direct binding of CoREST1 to SUMO‐2/3 contributes to gene‐specific repression by the LSD1/CoREST1/HDAC complex. Mol Cell 2009, 34:145–154.
Rodriguez, MS, Desterro, JM, Lain, S, Midgley, CA, Lane, DP, Hay, RT. SUMO‐1 modification activates the transcriptional response of p53. EMBO J 1999, 18:6455–6461.
Ouyang, J, Gill, G. SUMO engages multiple corepressors to regulate chromatin structure and transcription. Epigenetics 2009, 4:440–444.
Shiio, Y, Eisenman, RN. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci USA 2003, 100:13225–13230.
Hirano, Y, Murata, S, Tanaka, K, Shimizu, M, Sato, R. Sterol regulatory element‐binding proteins are negatively regulated through SUMO‐1 modification independent of the ubiquitin/26 S proteasome pathway. J Biol Chem 2003, 278:16809–16819.
Kim, J, Cantwell, CA, Johnson, PF, Pfarr, CM, Williams, SC. Transcriptional activity of CCAAT/enhancer‐binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J Biol Chem 2002, 277:38037–38044.
Muller, S, Berger, M, Lehembre, F, Seeler, JS, Haupt, Y, Dejean, A. c‐Jun and p53 activity is modulated by SUMO‐1 modification. J Biol Chem 2000, 275:13321–13329.
Sapetschnig, A, Rischitor, G, Braun, H, Doll, A, Schergaut, M, Melchior, F, Suske, G. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J 2002, 21:5206–5215.
Yang, SH, Jaffray, E, Hay, RT, Sharrocks, AD. Dynamic interplay of the SUMO and ERK pathways in regulating Elk‐1 transcriptional activity. Mol Cell 2003, 12:63–74.
Comerford, KM, Leonard, MO, Karhausen, J, Carey, R, Colgan, SP, Taylor, CT. Small ubiquitin‐related modifier‐1 modification mediates resolution of CREB‐dependent responses to hypoxia. Proc Natl Acad Sci USA 2003, 100:986–991.
Goodson, ML, Hong, Y, Rogers, R, Matunis, MJ, Park‐Sarge, OK, Sarge, KD. Sumo‐1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. J Biol Chem 2001, 276:18513–18518.
Hong, Y, Rogers, R, Matunis, MJ, Mayhew, CN, Goodson, ML, Park‐Sarge, OK, Sarge, KD. Regulation of heat shock transcription factor 1 by stress‐induced SUMO‐1 modification. J Biol Chem 2001, 276:40263–40267.
Yamamoto, H, Ihara, M, Matsuura, Y, Kikuchi, A. Sumoylation is involved in β‐catenin‐dependent activation of Tcf‐4. EMBO J 2003, 22:2047–2059.
Nathan, D, Ingvarsdottir, K, Sterner, DE, Bylebyl, GR, Dokmanovic, M, Dorsey, JA, Whelan, KA, Krsmanovic, M, Lane, WS, Meluh, PB, et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive‐acting histone modifications. Genes Dev 2006, 20:966–976.
Kalocsay, M, Hiller, NJ, Jentsch, S. Chromosome‐wide Rad51 spreading and SUMO‐H2A.Z‐dependent chromosome fixation in response to a persistent DNA double‐strand break. Mol Cell 2009, 33:335–343.
Hang, LE, Liu, X, Cheung, I, Yang, Y, Zhao, X. SUMOylation regulates telomere length homeostasis by targeting Cdc13. Nat Struct Mol Biol 2011, 18:920–926.
Xhemalce, B, Seeler, JS, Thon, G, Dejean, A, Arcangioli, B. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance. EMBO J 2004, 23:3844–3853.
Brown, PW, Hwang, K, Schlegel, PN, Morris, PL. Small ubiquitin‐related modifier (SUMO)‐1, SUMO‐2/3 and SUMOylation are involved with centromeric heterochromatin of chromosomes 9 and 1 and proteins of the synaptonemal complex during meiosis in men. Hum Reprod 2008, 23:2850–2857.
Zhang, XD, Goeres, J, Zhang, H, Yen, TJ, Porter, AC, Matunis, MJ. SUMO‐2/3 modification and binding regulate the association of CENP‐E with kinetochores and progression through mitosis. Mol Cell 2008, 29:729–741.
Liu, HW, Zhang, J, Heine, GF, Arora, M, Gulcin Ozer, H, Onti‐Srinivasan, R, Huang, K, Parvin, JD. Chromatin modification by SUMO‐1 stimulates the promoters of translation machinery genes. Nucleic Acids Res 2012, 40:10172–10186.
Halle, JP, Meisterernst, M. Gene expression: increasing evidence for a transcriptosome. Trends Genet 1996, 12:161–163.
Parvin, JD, Young, RA. Regulatory targets in the RNA polymerase II holoenzyme. Curr Opin Genet Dev 1998, 8:565–570.
Gall, JG, Bellini, M, Wu, Z, Murphy, C. Assembly of the nuclear transcription and processing machinery: Cajal bodies (coiled bodies) and transcriptosomes. Mol Biol Cell 1999, 10:4385–4402.
Bentley, DL. Coupling mRNA processing with transcription in time and space. Nat Rev Genet 2014, 15:163–175.
Darnell, JE Jr. Reflections on the history of pre‐mRNA processing and highlights of current knowledge: a unified picture. RNA 2013, 19:443–460.
Corden, JL, Patturajan, M. A CTD function linking transcription to splicing. Trends Biochem Sci 1997, 22:413–416.
Mortillaro, MJ, Blencowe, BJ, Wei, X, Nakayasu, H, Du, L, Warren, SL, Sharp, PA, Berezney, R. A hyperphosphorylated form of the large subunit of RNA polymerase II is associated with splicing complexes and the nuclear matrix. Proc Natl Acad Sci USA 1996, 93:8253–8257.
Chymkowitch, P, Nguea, AP, Aanes, H, Koehler, CJ, Thiede, B, Lorenz, S, Meza‐Zepeda, LA, Klungland, A, Enserink, JM. Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes. Genome Res 2015, 25:897–906.
Rosonina, E, Duncan, SM, Manley, JL. SUMO functions in constitutive transcription and during activation of inducible genes in yeast. Genes Dev 2010, 24:1242–1252.
Liu, HW, Banerjee, T, Guan, X, Freitas, MA, Parvin, JD. The chromatin scaffold protein SAFB1 localizes SUMO‐1 to the promoters of ribosomal protein genes to facilitate transcription initiation and splicing. Nucleic Acids Res 2015, 43:3605–3613.
Sanchez‐Alvarez, M, Montes, M, Sanchez‐Hernandez, N, Hernandez‐Munain, C, Sune, C. Differential effects of sumoylation on transcription and alternative splicing by transcription elongation regulator 1 (TCERG1). J Biol Chem 2010, 285:15220–15233.
Sims, RJ 3rd, Millhouse, S, Chen, CF, Lewis, BA, Erdjument‐Bromage, H, Tempst, P, Manley, JL, Reinberg, D. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre‐mRNA splicing. Mol Cell 2007, 28:665–676.
Lin, S, Coutinho‐Mansfield, G, Wang, D, Pandit, S, Fu, XD. The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct Mol Biol 2008, 15:819–826.
Saint‐Andre, V, Batsche, E, Rachez, C, Muchardt, C. Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons. Nat Struct Mol Biol 2011, 18:337–344.
Gonzalez, I, Munita, R, Agirre, E, Dittmer, TA, Gysling, K, Misteli, T, Luco, RF. A lncRNA regulates alternative splicing via establishment of a splicing‐specific chromatin signature. Nat Struct Mol Biol 2015, 22:370–376.
Graveley, BR. Sorting out the complexity of SR protein functions. RNA 2000, 6:1197–1211.
Zhong, XY, Wang, P, Han, J, Rosenfeld, MG, Fu, XD. SR proteins in vertical integration of gene expression from transcription to RNA processing to translation. Mol Cell 2009, 35:1–10.
Vassileva, MT, Matunis, MJ. SUMO modification of heterogeneous nuclear ribonucleoproteins. Mol Cell Biol 2004, 24:3623–3632.
Pelisch, F, Gerez, J, Druker, J, Schor, IE, Munoz, MJ, Risso, G, Petrillo, E, Westman, BJ, Lamond, AI, Arzt, E, et al. The serine/arginine‐rich protein SF2/ASF regulates protein sumoylation. Proc Natl Acad Sci USA 2010, 107:16119–16124.
Allo, M, Buggiano, V, Fededa, JP, Petrillo, E, Schor, I, de la Mata, M, Agirre, E, Plass, M, Eyras, E, Elela, SA, et al. Control of alternative splicing through siRNA‐mediated transcriptional gene silencing. Nat Struct Mol Biol 2009, 16:717–724.
Shukla, S, Kavak, E, Gregory, M, Imashimizu, M, Shutinoski, B, Kashlev, M, Oberdoerffer, P, Sandberg, R, Oberdoerffer, S. CTCF‐promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011, 479:74–79.
Ameur, A, Zaghlool, A, Halvardson, J, Wetterbom, A, Gyllensten, U, Cavelier, L, Feuk, L. Total RNA sequencing reveals nascent transcription and widespread co‐transcriptional splicing in the human brain. Nat Struct Mol Biol 2011, 18:1435–1440.
Iannone, C, Valcarcel, J. Chromatin`s thread to alternative splicing regulation. Chromosoma 2013, 122:465–474.
Khodor, YL, Rodriguez, J, Abruzzi, KC, Tang, CH, Marr, MT 2nd, Rosbash, M. Nascent‐seq indicates widespread cotranscriptional pre‐mRNA splicing in Drosophila. Genes Dev 2011, 25:2502–2512.
Takagaki, Y, Ryner, LC, Manley, JL. Four factors are required for 3`‐end cleavage of pre‐mRNAs. Genes Dev 1989, 3:1711–1724.
Shi, Y, Di Giammartino, DC, Taylor, D, Sarkeshik, A, Rice, WJ, Yates, JR 3rd, Frank, J, Manley, JL. Molecular architecture of the human pre‐mRNA 3` processing complex. Mol Cell 2009, 33:365–376.
Glover‐Cutter, K, Kim, S, Espinosa, J, Bentley, DL. RNA polymerase II pauses and associates with pre‐mRNA processing factors at both ends of genes. Nat Struct Mol Biol 2008, 15:71–78.
Vethantham, V, Rao, N, Manley, JL. Sumoylation modulates the assembly and activity of the pre‐mRNA 3` processing complex. Mol Cell Biol 2007, 27:8848–8858.
Vethantham, V, Rao, N, Manley, JL. Sumoylation regulates multiple aspects of mammalian poly(A) polymerase function. Genes Dev 2008, 22:499–511.
Zhang, D, Liang, Y, Xie, Q, Gao, G, Wei, J, Huang, H, Li, J, Gao, J, Huang, C. A novel post‐translational modification of nucleolin, SUMOylation at Lys‐294, mediates arsenite‐induced cell death by regulating gadd45α mRNA stability. J Biol Chem 2015, 290:4784–4800.
Bretes, H, Rouviere, JO, Leger, T, Oeffinger, M, Devaux, F, Doye, V, Palancade, B. Sumoylation of the THO complex regulates the biogenesis of a subset of mRNPs. Nucleic Acids Res 2014, 42:5043–5058.
Barski, A, Cuddapah, S, Cui, K, Roh, TY, Schones, DE, Wang, Z, Wei, G, Chepelev, I, Zhao, K. High‐resolution profiling of histone methylations in the human genome. Cell 2007, 129:823–837.
Tai, HH, Geisterfer, M, Bell, JC, Moniwa, M, Davie, JR, Boucher, L, McBurney, MW. CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins. Biochem Biophys Res Commun 2003, 308:170–176.
Nayler, O, Stratling, W, Bourquin, JP, Stagljar, I, Lindemann, L, Jasper, H, Hartmann, AM, Fackelmayer, FO, Ullrich, A, Stamm, S. SAF‐B protein couples transcription and pre‐mRNA splicing to SAR/MAR elements. Nucleic Acids Res 1998, 26:3542–3549.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Roles for SUMO in pre‐mRNA processing

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox