FUS (fused in Sarcoma) is a Component of the Cellular Response to Topoisomerase I-induced DNA Breakage and Transcriptional Stress

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2019 Feb 28

PMID 30808650

Citations 13

Authors

Maria Isabel Martinez-Macias

Duncan Aq Moore

Ryan L Green

Fernando Gomez-Herreros

Marcel Naumann

Andreas Hermann

Philip Van Damme

Majid Hafezparast

Keith W Caldecott

Affiliations

Soon will be listed here.

Abstract

FUS (fused in sarcoma) plays a key role in several steps of RNA metabolism, and dominant mutations in this protein are associated with neurodegenerative diseases. Here, we show that FUS is a component of the cellular response to topoisomerase I (TOP1)-induced DNA breakage; relocalising to the nucleolus in response to RNA polymerase II (Pol II) stalling at sites of TOP1-induced DNA breaks. This relocalisation is rapid and dynamic, reversing following the removal of TOP1-induced breaks and coinciding with the recovery of global transcription. Importantly, FUS relocalisation following TOP1-induced DNA breakage is associated with increased FUS binding at sites of RNA polymerase I transcription in ribosomal DNA and reduced FUS binding at sites of RNA Pol II transcription, suggesting that FUS relocates from sites of stalled RNA Pol II either to regulate pre-mRNA processing during transcriptional stress or to modulate ribosomal RNA biogenesis. Importantly, FUS-mutant patient fibroblasts are hypersensitive to TOP1-induced DNA breakage, highlighting the possible relevance of these findings to neurodegeneration.

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References

Schwartz J, Ebmeier C, Podell E, Heimiller J, Taatjes D, Cech T . FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 2012; 26(24):2690-5. PMC: 3533074. DOI: 10.1101/gad.204602.112. View

Katyal S, Lee Y, Nitiss K, Downing S, Li Y, Shimada M . Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat Neurosci. 2014; 17(6):813-21. PMC: 4074009. DOI: 10.1038/nn.3715. View

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

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

Sun S, Ling S, Qiu J, Albuquerque C, Zhou Y, Tokunaga S . ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun. 2015; 6:6171. PMC: 4338613. DOI: 10.1038/ncomms7171. View

Shav-Tal Y, Blechman J, Darzacq X, Montagna C, Dye B, Patton J . Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition. Mol Biol Cell. 2005; 16(5):2395-413. PMC: 1087244. DOI: 10.1091/mbc.e04-11-0992. View

Pommier Y, Leo E, Zhang H, Marchand C . DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010; 17(5):421-33. PMC: 7316379. DOI: 10.1016/j.chembiol.2010.04.012. View

Hill S, Mordes D, Cameron L, Neuberg D, Landini S, Eggan K . Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage. Proc Natl Acad Sci U S A. 2016; 113(48):E7701-E7709. PMC: 5137757. DOI: 10.1073/pnas.1611673113. View

Patel A, Lee H, Jawerth L, Maharana S, Jahnel M, Hein M . A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015; 162(5):1066-77. DOI: 10.1016/j.cell.2015.07.047. View

10.

Gomez-Herreros F, Schuurs-Hoeijmakers J, McCormack M, Greally M, Rulten S, Romero-Granados R . TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet. 2014; 46(5):516-21. DOI: 10.1038/ng.2929. View

11.

Bertolotti A, Lutz Y, Heard D, Chambon P, Tora L . hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J. 1996; 15(18):5022-31. PMC: 452240. View

12.

Yang L, Gal J, Chen J, Zhu H . Self-assembled FUS binds active chromatin and regulates gene transcription. Proc Natl Acad Sci U S A. 2014; 111(50):17809-14. PMC: 4273402. DOI: 10.1073/pnas.1414004111. View

13.

Chan Y, Hieter P, Stirling P . Mechanisms of genome instability induced by RNA-processing defects. Trends Genet. 2014; 30(6):245-53. PMC: 4039741. DOI: 10.1016/j.tig.2014.03.005. View

14.

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

15.

Mastrocola A, Kim S, Trinh A, Rodenkirch L, Tibbetts R . The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage. J Biol Chem. 2013; 288(34):24731-41. PMC: 3750169. DOI: 10.1074/jbc.M113.497974. View

16.

Deng Q, Holler C, Taylor G, Hudson K, Watkins W, Gearing M . FUS is phosphorylated by DNA-PK and accumulates in the cytoplasm after DNA damage. J Neurosci. 2014; 34(23):7802-13. PMC: 4044245. DOI: 10.1523/JNEUROSCI.0172-14.2014. View

17.

Takashima H, Boerkoel C, John J, Saifi G, Salih M, Armstrong D . Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002; 32(2):267-72. DOI: 10.1038/ng987. View

18.

Stewart A, HERRERA R, Nordheim A . Rapid induction of c-fos transcription reveals quantitative linkage of RNA polymerase II and DNA topoisomerase I enzyme activities. Cell. 1990; 60(1):141-9. DOI: 10.1016/0092-8674(90)90724-s. View

19.

El-Khamisy S, Saifi G, Weinfeld M, Johansson F, Helleday T, Lupski J . Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature. 2005; 434(7029):108-13. DOI: 10.1038/nature03314. View

20.

Rulten S, Rotheray A, Green R, Grundy G, Moore D, Gomez-Herreros F . PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. Nucleic Acids Res. 2013; 42(1):307-14. PMC: 3874156. DOI: 10.1093/nar/gkt835. View