FUS Binds the CTD of RNA Polymerase II and Regulates Its Phosphorylation at Ser2

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2012 Dec 20

PMID 23249733

Citations 137

Authors

Jacob C Schwartz

Christopher C Ebmeier

Elaine R Podell

Joseph Heimiller

Dylan J Taatjes

Thomas R Cech

Affiliations

Soon will be listed here.

Abstract

Mutations in the RNA-binding protein FUS (fused in sarcoma)/TLS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the normal role of FUS is incompletely understood. We found that FUS binds the C-terminal domain (CTD) of RNA polymerase II (RNAP2) and prevents inappropriate hyperphosphorylation of Ser2 in the RNAP2 CTD at thousands of human genes. The loss of FUS leads to RNAP2 accumulation at the transcription start site and a shift in mRNA isoform expression toward early polyadenylation sites. Thus, in addition to its role in alternative RNA splicing, FUS has a general function in orchestrating CTD phosphorylation during RNAP2 transcription.

Citing Articles

Navigating a complex dance: the interplay between RNA-binding proteins and T cells in oral epithelial plasticity.

Vijayakumar A, Vasudevan S, John S, Ozbun M, Bartee E, Palanisamy V Immunometabolism (Cobham). 2025; 7(1):e00054.

PMID: 39816132 PMC: 11731067. DOI: 10.1097/IN9.0000000000000054.

FUS-Mediated Inhibition of Myogenesis Elicited by Suppressing TNNT1 Production.

Ji E, Pandey P, Martindale J, Yang X, Yang J, Tsitsipatis D Mol Cell Biol. 2024; 44(9):391-409.

PMID: 39133076 PMC: 11376412. DOI: 10.1080/10985549.2024.2383296.

Liquid-liquid phase separation in diseases.

Zhang X, Yuan L, Zhang W, Zhang Y, Wu Q, Li C MedComm (2020). 2024; 5(7):e640.

PMID: 39006762 PMC: 11245632. DOI: 10.1002/mco2.640.

Modulation of diverse biological processes by CPSF, the master regulator of mRNA 3' ends.

Liu L, Manley J RNA. 2024; 30(9):1122-1140.

PMID: 38986572 PMC: 11331416. DOI: 10.1261/rna.080108.124.

Endogenous EWSR1 Exists in Two Visual Modalities That Reflect Its Associations with Nucleic Acids and Concentration at Sites of Active Transcription.

Sundara Rajan S, Ebegboni V, Pichling P, Ludwig K, Jones T, Chari R Mol Cell Biol. 2024; 44(3):103-122.

PMID: 38506112 PMC: 10986767. DOI: 10.1080/10985549.2024.2315425.

References

Hoell J, Larsson E, Runge S, Nusbaum J, Duggimpudi S, Farazi T . RNA targets of wild-type and mutant FET family proteins. Nat Struct Mol Biol. 2011; 18(12):1428-31. PMC: 3230689. DOI: 10.1038/nsmb.2163. View

Kim H, Erickson B, Luo W, Seward D, Graber J, Pollock D . Gene-specific RNA polymerase II phosphorylation and the CTD code. Nat Struct Mol Biol. 2010; 17(10):1279-86. PMC: 3048030. DOI: 10.1038/nsmb.1913. View

Yamazaki T, Chen S, Yu Y, Yan B, Haertlein T, Carrasco M . FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2012; 2(4):799-806. PMC: 3483417. DOI: 10.1016/j.celrep.2012.08.025. View

Kwiatkowski Jr T, Bosco D, Leclerc A, Tamrazian E, Vanderburg C, Russ C . Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009; 323(5918):1205-8. DOI: 10.1126/science.1166066. View

Wang X, Arai S, Song X, Reichart D, Du K, Pascual G . Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature. 2008; 454(7200):126-30. PMC: 2823488. DOI: 10.1038/nature06992. View

Lagier-Tourenne C, Polymenidou M, Hutt K, Vu A, Baughn M, Huelga S . Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012; 15(11):1488-97. PMC: 3586380. DOI: 10.1038/nn.3230. View

Munoz M, Perez Santangelo M, Paronetto M, Mata M, Pelisch F, Boireau S . DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation. Cell. 2009; 137(4):708-20. DOI: 10.1016/j.cell.2009.03.010. View

Marshall N, Price D . Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem. 1995; 270(21):12335-8. DOI: 10.1074/jbc.270.21.12335. View

Reppas N, Wade J, Church G, Struhl K . The transition between transcriptional initiation and elongation in E. coli is highly variable and often rate limiting. Mol Cell. 2006; 24(5):747-757. DOI: 10.1016/j.molcel.2006.10.030. View

10.

Yamaguchi Y, Takagi T, Wada T, Yano K, Furuya A, Sugimoto S . NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell. 1999; 97(1):41-51. DOI: 10.1016/s0092-8674(00)80713-8. View

11.

Rahl P, Lin C, Seila A, Flynn R, McCuine S, Burge C . c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45. PMC: 2864022. DOI: 10.1016/j.cell.2010.03.030. View

12.

Cozzolino M, Carri M . Mitochondrial dysfunction in ALS. Prog Neurobiol. 2011; 97(2):54-66. DOI: 10.1016/j.pneurobio.2011.06.003. View

13.

Vance C, Rogelj B, Hortobagyi T, De Vos K, Nishimura A, Sreedharan J . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009; 323(5918):1208-1211. PMC: 4516382. DOI: 10.1126/science.1165942. View

14.

Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z . The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 2011; 25(20):2158-72. PMC: 3205586. DOI: 10.1101/gad.16962311. View

15.

Kaneko S, Manley J . The mammalian RNA polymerase II C-terminal domain interacts with RNA to suppress transcription-coupled 3' end formation. Mol Cell. 2005; 20(1):91-103. DOI: 10.1016/j.molcel.2005.08.033. View

16.

Ahn S, Kim M, Buratowski S . Phosphorylation of serine 2 within the RNA polymerase II C-terminal domain couples transcription and 3' end processing. Mol Cell. 2004; 13(1):67-76. DOI: 10.1016/s1097-2765(03)00492-1. View

17.

Mackenzie I, Rademakers R, Neumann M . TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010; 9(10):995-1007. DOI: 10.1016/S1474-4422(10)70195-2. View

18.

Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, Shibata A . Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep. 2012; 2:529. PMC: 3402842. DOI: 10.1038/srep00529. View

19.

Bartkowiak B, Liu P, Phatnani H, Fuda N, Cooper J, Price D . CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010; 24(20):2303-16. PMC: 2956209. DOI: 10.1101/gad.1968210. View

20.

Y Tan A, Riley T, Coady T, Bussemaker H, Manley J . TLS/FUS (translocated in liposarcoma/fused in sarcoma) regulates target gene transcription via single-stranded DNA response elements. Proc Natl Acad Sci U S A. 2012; 109(16):6030-5. PMC: 3341064. DOI: 10.1073/pnas.1203028109. View