G-quadruplex structural motifs modulate protein–RNA interactions within the transcriptome | Genome Biology

  • Nakaya T, Maragkakis M. Amyotrophic lateral sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity. Sci Rep. 2018;8:15575.

    PubMed 
    PubMed Central 

    Google Scholar 

  • An H, Skelt L, Notaro A, Highley JR, Fox AH, La Bella V, et al. ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles. Acta Neuropathol Commun. 2019;7:7.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kamelgarn M, Chen J, Kuang L, Jin H, Kasarskis EJ, Zhu H. ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay. Proc Natl Acad Sci U S A. 2018;115:E11904–13.

    Google Scholar 

  • Xiong D, Wu YB, Jin C, Li JJ, Gu J, Liao YF, et al. Elevated FUS/TLS expression is negatively associated with E-cadherin expression and prognosis of patients with non-small cell lung cancer. Oncol Lett. 2018;16:1791–800.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Brooke GN, Culley RL, Dart DA, Mann DJ, Gaughan L, McCracken SR, et al. FUS/TLS is a novel mediator of androgen-dependent cell-cycle progression and prostate cancer growth. Cancer Res. 2011;71:914–24.

    PubMed 

    Google Scholar 

  • Rabbitts TH, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 1993;4:175–80.

    PubMed 

    Google Scholar 

  • Schöpf J, Uhrig S, Heilig CE, Lee K-S, Walther T, Carazzato A, et al. Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions. Nat Commun. 2024;15:51.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang Y, Zhang X-F, Wang D-Y, Zhu Y, Chen L, Zhang J-J. Long noncoding RNA SOX2OT promotes pancreatic cancer cell migration and invasion through destabilizing FUS protein via ubiquitination. Cell Death Discov. 2021;7:1–9.

    Google Scholar 

  • Rezvykh AP, Ustyugov AA, Chaprov KD, Teterina EV, Nebogatikov VO, Spasskaya DS, et al. Cytoplasmic aggregation of mutant FUS causes multistep RNA splicing perturbations in the course of motor neuron pathology. Nucleic Acids Res. 2023;51:5810–30.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Rhine K, Makurath MA, Liu J, Skanchy S, Lopez C, Catalan KF, et al. ALS/FTLD-linked mutations in FUS glycine residues cause accelerated gelation and reduced interactions with wild-type FUS. Mol Cell. 2020;80:666-681.e8.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Birsa N, Ule AM, Garone MG, Tsang B, Mattedi F, Chong PA, et al. FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Sci Adv. 2021;7:eabf8660.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Burke KA, Janke AM, Rhine CL, Fawzi NL. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol Cell. 2015;60:231–41.

  • Murray DT, Kato M, Lin Y, Thurber KR, Hung I, McKnight SL, et al. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation of low-complexity domains. Cell. 2017;171:615-627.e16.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Loughlin FE, Lukavsky PJ, Kazeeva T, Reber S, Hock EM, Colombo M, et al. The solution structure of FUS bound to RNA reveals a bipartite mode of RNA recognition with both sequence and shape specificity. Mol Cell. 2019;73(490–504):e6.

    Google Scholar 

  • Masuda A, Takeda J, Okuno T, Okamoto T, Ohkawara B, Ito M, et al. Position-specific binding of FUS to nascent RNA regulates mRNA length. Genes Dev. 2015;29:1045–57.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Iko Y, Kodama TS, Kasai N, Oyama T, Morita EH, Muto T, et al. Domain architectures and characterization of an RNA-binding protein, TLS. J Biol Chem. 2004;279:44834–40.

    PubMed 

    Google Scholar 

  • Lerga A, Hallier M, Delva L, Orvain C, Gallais I, Marie J, et al. Identification of an RNA binding specificity for the potential splicing factor TLS. J Biol Chem. 2001;276:6807–16.

    PubMed 

    Google Scholar 

  • Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15:1488–97.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhou Y, Liu S, Liu G, Öztürk A, Hicks GG. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013;9:e1003895.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Takeda J, Masuda A, Ohno K. Six GU-rich (6GUR) FUS-binding motifs detected by normalization of CLIP-seq by Nascent-seq. Gene. 2017;618:57–64.

    PubMed 

    Google Scholar 

  • Sanchez de Groot N, Armaos A, Graña-Montes R, Alriquet M, Calloni G, Vabulas RM, et al. RNA structure drives interaction with proteins. Nat Commun. 2019;10:3246.

  • Smola MJ, Christy TW, Inoue K, Nicholson CO, Friedersdorf M, Keene JD, et al. Shape reveals transcript-wide interactions, complex structural domains, and protein interactions across the Xist lncRNA in living cells. PNAS. 2016;113:10322–7.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Takahama K, Oyoshi T. Specific binding of modified RGG domain in TLS/FUS to G-quadruplex RNA: tyrosines in RGG domain recognize 2’-OH of the riboses of loops in G-quadruplex. J Am Chem Soc. 2013;135:18016–9.

    PubMed 

    Google Scholar 

  • Bhattacharyya D, Mirihana Arachchilage G, Basu S. Metal cations in G-quadruplex folding and stability. Front Chem. 2016;4.

  • Hardin CC, Watson T, Corregan M, Bailey C. Cation-dependent transition between the quadruplex and Watson-Crick hairpin forms of d(CGCG3GCG). Biochemistry. 1992;31:833–41.

    PubMed 

    Google Scholar 

  • Takahama K, Takada A, Tada S, Shimizu M, Sayama K, Kurokawa R, et al. Regulation of telomere length by G-quadruplex telomere DNA- and TERRA-binding protein TLS/FUS. Chem Biol. 2013;20:341–50.

    PubMed 

    Google Scholar 

  • Yagi R, Miyazaki T, Oyoshi T. G-quadruplex binding ability of TLS/FUS depends on the beta-spiral structure of the RGG domain. Nucleic Acids Res. 2018;46:5894–901.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kondo K, Mashima T, Oyoshi T, Yagi R, Kurokawa R, Kobayashi N, et al. Plastic roles of phenylalanine and tyrosine residues of TLS/FUS in complex formation with the G-quadruplexes of telomeric DNA and TERRA. Sci Rep. 2018;8:2864.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ghosh M, Singh M. RGG-box in hnRNPA1 specifically recognizes the telomere G-quadruplex DNA and enhances the G-quadruplex unfolding ability of UP1 domain. Nucleic Acids Res. 2018;46:10246–61.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Masuzawa T, Oyoshi T. Roles of the RGG domain and RNA recognition motif of nucleolin in G-quadruplex stabilization. ACS Omega. 2020;5:5202–8.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Takahama K, Miyawaki A, Shitara T, Mitsuya K, Morikawa M, Hagihara M, et al. G-quadruplex DNA- and RNA-specific-binding proteins engineered from the RGG domain of TLS/FUS. ACS Chem Biol. 2015;10:2564–9.

    PubMed 

    Google Scholar 

  • Imperatore JA, McAninch DS, Valdez-Sinon AN, Bassell GJ, Mihailescu MR. FUS recognizes G quadruplex structures within neuronal mRNAs. Front Mol Biosci. 2020;7:6.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Jutzi D, Campagne S, Schmidt R, Reber S, Mechtersheimer J, Gypas F, et al. Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis. Nat Commun. 2020;11:6341.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Sahadevan S, Hembach KM, Tantardini E, Pérez-Berlanga M, Hruska-Plochan M, Megat S, et al. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS. Nat Commun. 2021;12:1–17.

    Google Scholar 

  • Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A, Poser I, et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science. 2018;360:918–21.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ganser LR, Niaki AG, Yuan X, Huang E, Deng D, Djaja NA, et al. The roles of FUS-RNA binding domain and low complexity domain in RNA-dependent phase separation. Structure. 2024;32:177-187.e5.

    PubMed 

    Google Scholar 

  • Anger AM, Armache J-P, Berninghausen O, Habeck M, Subklewe M, Wilson DN, et al. Structures of the human and Drosophila 80S ribosome. Nature. 2013;497:80–5.

    PubMed 

    Google Scholar 

  • Rozen S, Füzesi-Levi MG, Ben-Nissan G, Mizrachi L, Gabashvili A, Levin Y, et al. CSNAP is a stoichiometric subunit of the COP9 signalosome. Cell Rep. 2015;13:585–98.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Breen EC, Tang K. Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro. J Cell Biochem. 2003;88:848–54.

    PubMed 

    Google Scholar 

  • Grahn THM, Niroula A, Végvári Á, Oburoglu L, Pertesi M, Warsi S, et al. S100A6 is a critical regulator of hematopoietic stem cells. Leukemia. 2020;34:3323–37.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Mergny J-L, Li J, Lacroix L, Amrane S, Chaires JB. Thermal difference spectra: a specific signature for nucleic acid structures. Nucleic Acids Res. 2005;33:e138.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kypr J, Kejnovská I, Renčiuk D, Vorlíčková M. Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res. 2009;37:1713–25.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Schwartz JC, Wang X, Podell ER, Cech TR. RNA seeds higher-order assembly of FUS protein. Cell Rep. 2013;5:918–25.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ishiguro A, Katayama A, Ishihama A. Different recognition modes of G-quadruplex RNA between two ALS/FTLD-linked proteins TDP-43 and FUS. FEBS Lett. 2021;595:310–23.

    PubMed 

    Google Scholar 

  • Sévigny M, Bourdeau Julien I, Venkatasubramani JP, Hui JB, Dutchak PA, Sephton CF. Fus contributes to mTOR-dependent inhibition of translation. J Biol Chem. 2020;295:18459–73.

    PubMed 

    Google Scholar 

  • Piol D, Robberechts T, Da Cruz S. Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis. Neuron. 2023;111:1355–80.

    PubMed 

    Google Scholar 

  • Fujino Y, Ueyama M, Ishiguro T, Ozawa D, Ito H, Sugiki T, et al. FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD. Eisen MB, editor. eLife. 2023;12:RP84338.

  • López-Erauskin J, Tadokoro T, Baughn MW, Myers B, McAlonis-Downes M, Chillon-Marinas C, et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron. 2018;100:816-830.e7.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ward CL, Boggio KJ, Johnson BN, Boyd JB, Douthwright S, Shaffer SA, et al. A loss of FUS/TLS function leads to impaired cellular proliferation. Cell Death Dis. 2014;5:e1572.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Füzesi-Levi MG, Fainer I, Ivanov Enchev R, Ben-Nissan G, Levin Y, Kupervaser M, et al. Csnap, the smallest CSN subunit, modulates proteostasis through cullin-RING ubiquitin ligases. Cell Death Differ. 2020;27:984–98.

    PubMed 

    Google Scholar 

  • Bennett EJ, Rush J, Gygi SP, Harper JW. Dynamics of Cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell. 2010;143:951–65.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Picchiarelli G, Demestre M, Zuko A, Been M, Higelin J, Dieterlé S, et al. Fus-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis. Nat Neurosci. 2019;22:1793–805. https://doi.org/10.1038/s41593-019-0498-9.

  • Belmonte-Reche E, Morales JC. G4-iM Grinder: when size and frequency matter. G-quadruplex, i-Motif and higher order structure search and analysis tool. NAR Genom Bioinform. 2020;2:lqz005.

    PubMed 

    Google Scholar 

  • Bhatt U, Evans CW, Cucchiarini A, Gros J, Iyer KS, Mergny J-L, et al. G-quadruplex structural motifs modulate protein-RNA interactions within the transcriptome [RIP-seq]. Gene Expression Omnibus. 2025. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE284272

  • Bhatt U, Evans CW, Cucchiarini A, Gros J, Iyer KS, Mergny J-L, et al. G-quadruplex structural motifs modulate protein-RNA interactions within the transcriptome [Datasets]. 2025. Zenodo. https://doi.org/10.5281/zenodo.17069363.

  • Jutzi D, Ruepp M-D. Transcriptome-wide identification of nuclear and cytoplasmic RNA-binding sites of FUS RBD-only constructs [CLIP-seq]. Gene Expression Omnibus. 2020. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139263.

  • Continue Reading