Cyril Dominguez

Personal Details

Cyril DominguezAssociate Professor
Cyril Dominguez Headshot 2.0

Department: Molecular and Cell Biology
Telephone: +44 (0)116 229 7073
Email: cyril.dominguez@le.ac.uk
Web Links: https://www2.le.ac.uk/departments/molcellbiol

Biography

I am a structural biologist interested mainly in protein-RNA interactions involved in the regulation of alternative splicing. I obtained my BSc and MSc in Biochemistry from the University of Aix-Marseille (France). In 2000, I moved to the University of Utrecht (The Netherlands) to do a PhD under the supervision of Rob Kaptein, Rolf Boelens and Alexandre Bonvin. During that time, I developed a novel protein-protein docking software, HADDOCK. After my PhD in 2004, I joined the laboratory of Fred Allain at the ETH Zurich (Switzerland) where I studied the interaction between the splicing factor hnRNP F and G-tract RNAs. In 2010, I obtained an MRC Career Development Award Fellowship to initiate my own research programme at the University of Leicester. My research focused on i) the interaction between the splicing factor Sam68 and its target RNA and ii) the role of RNA G-quadruplexes in the regulation of alternative splicing. In 2015, I became a lecturer at the University of Leicester.

Qualifications

  • BSc Biochemistry (University of Aix-Marseille)
  • MSc Nutritional Biochemistry (University of Aix-Marseille)
  • PhD in Structural Biology (University of Utrecht)

Publications

  1. Weldon C,. Dacanay J.G., Gokhale V., Boddupally P.V.L., Behm-Ansmant I., Burley G.A., Branlant C., Hurley L.H., Dominguez C., Eperon I.C. (2018). Specific G-quadruplex ligands modulate the alternative splicing of Bcl-x. Nucleic Acids Res., 46, 886-96
  2. Danilenko M., Dalgliesh C., Pagliarini V., Naro C., Ehrmann I., Feracci M., Kheirollahi-Chadegani M., Tyson-Capper A., Clowry G.J., Fort P., Dominguez C., Sette C., Elliott D.J. (2017). Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control. Nucleic Acids Res., 45, 4120-30
  3. Weldon C., Eperon I.C., Dominguez C. (2016). Do we know whether G-quadruplexes actually form in long functional RNA molecules? Biochem Soc Trans, 44, 1761-68
  4. Weldon C., Behn-Ansmant I., Burley G.A., Hurley L.H., Branlant C., Eperon I.C., and Dominguez C. (2016). Identification of G-quadruplexes using 7-deaza-guanine substituted RNA. Nat. Chem. Biol., 13, 18-20
  5. Feracci M., Foot J.N., Grellscheid S.N., Danilenko M., Stehle R., Gonchar O., Kang H.S., Meyer N.H., Liu Y., Lahat A., Sattler M., Eperon I.C., Elliott D.J., and Dominguez C. (2016). Structural basis of RNA recognition and dimerization by the STAR proteins T-STAR and Sam68. Nat. Comms, 7, 10355
  6. Feracci M., Foot J.N., and Dominguez C. (2014). Structural investigations of the RNA-binding properties of STAR proteins. Biochem. Soc. Trans., 42(4), 1141-6
  7. Foot J.N.*, Feracci M.*, and Dominguez C. (2014). Screening protein – single stranded RNA complexes by NMR spectroscopy for structure determination. Methods, 65, 288-301.
  8. Theler D., Dominguez C., Blatter M., Boudet J., and Allain F.H-T (2014). Solution structure of the YTH domain in complex with N6-methyladenosine RNA: a reader of methylated RNA. Nucleic Acids Res., 42, 13911-9
  9. Back R., Dominguez C., Rothé B., Bobo C., Beaufils C., Moréra S., Meyer P., Charpentier P., Branlant C., Allain F.H.-T., and Manival X. (2013). NMR high resolution structures of free Tah1 and Tah1 bound to the Hsp90 C-terminal tail explains how Hsp90 recognizes the R2TP complex. Structure, 21, 1834-47.
  10. Samatanga B., Dominguez C., Jelezarov I., Allain F.H-.T. (2013) The high kinetic stability of a G-quadruplex limits hnRNP F qRRM3 binding to G-tract RNA Nucleic Acids Res., 41, 2505-16
  11. Schubert M., Dominguez C., Duss O., Ravindranathan S. and Allain F.H.-T (2011) Structure determination and dynamics of protein-RNA complexes using NMR spectroscopy Advances in Biomedical Spectroscopy, Volume 3, 249-278.
  12. Cléry A., Jayne S., Benderska N., Dominguez C. , Stamm S. and Allain F.H.-T. (2011) Molecular basis of purine-rich RNA recognition by the human SR-like protein Tra2-beta1 Nat. Struct. Mol. Biol., 18, 443-50
  13. Dominguez C.*, Schubert M.*, Duss O.*, Ravindranathan S.* and Allain F.H.-T* (2011) Structure determination and dynamics of protein-RNA complexes by NMR spectroscopy Prog. Nuc. Mag. Res. Spec., 58, 1-61.
  14. Dominguez C., Fisette J.F., Chabot B., Allain F.H.-T. (2010). Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs Nat. Struct. Mol. Biol., 17, 853-61
  15. Dominguez C. and Allain F.H.-T. (2006) NMR structure of the three quasi RNA Recognition Motifs (qRRMs) of human hnRNP F and interaction studies with Bcl-x G-tract RNA: A novel mode of RNA recognition Nucleic Acids Res., 34, 3634-3645
  16. Dominguez C., and Allain F.H.-T. (2005) Resonance assignments of the N-terminal RNA recognition motifs (RRM) of the human heterogeneous nuclear ribonucleoprotein F (HnRNP F) J. Biomol. NMR, 33, 282
  17. Maris C.*, Dominguez C.* and Allain F.H.-T. (2005) The RNA recognition motif, a plastic RNA binding platform to regulate posttranscriptional gene expression FEBS Journal, 272, 2118-2131
  18. van Dijk A.D.J., de Vries S.J., Dominguez C., Chen H., Zhou H.X. and Bonvin A.M.J.J. (2005) Data-driven docking: HADDOCK’s adventures in CAPRI Proteins, 60, 232-23
  19. Houben K., Wasielewski E., Dominguez C., Kellenberger E., Atkinson R.A., Timmers H.Th.M., Kieffer B. and Boelens R. (2005) Dynamics and metal exchange properties of C4C4 RING domains from CNOT4 and the p44 subunit of TFIIH J. Mol. Biol., 349(3), 621-637
  20. Kellenberger E., Dominguez C., Fribourg S., Wasielewski E., Moras D., Poterszman A., Boelens R. and Kieffer B. (2005) Solution structure of the C-terminal domain of TFIIH P44 subunit reveals a novel type of C4C4 ring domain involved in protein-protein interactions J. Biol. Chem., 280(21), 20785-20792
  21. Houben K.*, Dominguez C.*, van Schaik F.M.A., Timmers H.Th.M., Bonvin A.M.J.J. and Boelens R. (2004) Solution structure of the Ubiquitin-conjugating enzyme UbcH5B J. Mol. Biol., 344(2), 513-526
  22. Dominguez C., Bonvin A.M.J.J., Winkler G.S., van Schaik F.M.A., Timmers H.Th.M. and Boelens R. (2004) Structural model of the UbcH5B/CNOT4 complex revealed by combining NMR, mutagenesis and docking approaches Structure, 12(4), 633-644
  23. Winkler G.S., Albert T.K., Dominguez C., Legtenberg Y.I.A., Boelens R. and Timmers H.Th.M. (2004) An altered-specificity Ubiquitin-conjugating enzyme/Ubiquitin-protein ligase pair J. Mol. Biol., 337(1), 157-165
  24. Dominguez C., Folkers G.E. and Boelens R. (2003) RING Domain Proteins Contribution to "Handbook of metalloproteins", Volume 3, John Wiley and Son, 338-35
  25. Dominguez C., Boelens R. and Bonvin A.M.J.J. (2003) HADDOCK: A Protein-Protein Docking Approach Based on Biochemical or Biophysical Information J. Am. Chem. Soc., 125(7) pp. 1731 - 1737
  26. Dominguez C., Sebban-Kreuzer C., Bornet O., Kerfelec B., Chapus C. and Guerlesquin F. (2000) Interactions of bile salt micelles and colipase studied through intermolecular nOes FEBS Letters, 482 (1-2), pp. 109-112

Other Publications

  1. Dominguez C. (2004) NMR-based docking of protein-protein complexes: the human UbcH5B-CNOT4 ubiquitination complex. Ph.D Thesis, Utrecht University ISBN: 90-393-3721-7

Research

Our laboratory is interested in the structure-function relationship of RNA structure and RNA binding proteins involved in the regulation of alternative splicing.

In eukaryotes, gene transcription produces a pre-messenger RNA (pre-mRNA) that contains alternating sequences, the introns and the exons. Alternative splicing describes the regulated process of differential inclusion or exclusion of certain regions of the pre-mRNA. This process allows the production, from a single gene, of many protein isoforms that can have different cellular functions. Alternative splicing is thus an important source of protein diversity from a limited number of genes. Recently, it was shown that more than 90% of the protein-coding genes in the human genome undergo alternative splicing and misregulation of alternative splicing is responsible to many genetic diseases, such as cancer.

Recently, we have solved the structure of the splicing factors Sam68 and T-STAR in complex with their RNA target (Feracci, Nat. Commun., 2016). Sam68 and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins. T-STAR is a tissue-specific paralogue that regulates the alternative splicing of neuronal pre-mRNAs. STAR proteins differ from most splicing factors, in that they contain a single RNA-binding domain. Their specificity of RNA recognition is thought to arise from their property to homodimerize, but how dimerization influences their function remains unknown. We have establish at atomic resolution how T-STAR and Sam68 bind to RNA, revealing an unexpected mode of dimerization different from other members of the STAR family. We further demonstrate that this unique dimerization interface is crucial for their biological activity in splicing regulation, and suggest that the increased RNA affinity through dimer formation is a crucial parameter enabling these proteins to select their functional targets within the transcriptome.

Image A
Structure of the RNA binding protein T-STAR in complex with its RNA target

G-quadruplexes (G4s) are small, four-stranded structures that can form in DNA and RNA molecules and have been shown to be involved in cancer progression. Modulating their stability could open up new ways of understanding and manipulating splicing towards therapeutic benefits. However, it has been very difficult to prove that they form in long RNA molecules in functional splicing conditions, and nothing is known of how they might affect splicing. We have recently published a new method, called FOLDeR, that allowed us to establish that specific regions of do form G4s in the pre-mRNA of Bcl-x, an oncogene expressing two isoforms of protein: one promotes cell survival and the other promotes apoptosis (Weldon et al, Nat Chem Biol, 2017). We have also identified a drug-like small molecule that binds these G4s and switches the splicing of Bcl-x to express the pro-apoptotic isoform and promotes cancer cell death (Weldon et al, Nucleic Acids Res., 2018).

Image B
The group of Dr. Dominguez has developed a novel method to characterize 
G-quadruplexes in long functional RNAs and in functional conditions.

> See my LISCB Research Page

Supervision

Current Group Members

  • Mohammed Bhogodia (PhD student)
  • Hatice Esenkaya (PhD student)
  • Mohamed Hassan (PhD student)
  • Ayesha Hasan (PhD student)
  • Nora Kogelnik (Technician)
  • Adam Lightfoot (PhD student)
  • Mishal Tariq (PhD student)

Previous Group Members

  • Mikael Feracci (currently research fellow at ISCB, Marseille, France)
  • Jaelle Foot (currently researcher at Adaptimmune)
  • Carika Weldon (Currently lecturer at De Montfort University, Leicester)
  • Oksana Gonchar (Currently postdoc at the University of Leicester)

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Contact Details

Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

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