Alfredo De Biasio

Personal Details

Dr. Alfredo De BiasioLecturer in Structural Biology

Alfredo De Biasio

Telephone: +44 (0)116 252 5391
Department: Molecular and Cell Biology
Email: adb43@leicester.ac.uk
Web links:

Biography

I am a lecturer in Structural Biology. I own a M.Sc. in Chemistry from the University of Padua, Italy, and a Ph.D. from the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy (obtained in 2008). Most of my postdoctoral work, mainly carried out at CIC bioGUNE in Spain, has been devoted to the study of the structure and function of DNA replication proteins, in particular of the human sliding clamp PCNA and its complexes. In 2015, I have been awarded a 2-year AIRC-Marie Curie Reintegration Fellowship from the Italian Association for Cancer Research to work at Elettra-Sincrotrone Trieste, Italy, where I coordinated an international project involving three laboratories. The results of this project, which combined experimental and computational methods, have provided a structural basis for the mechanism of PCNA sliding on DNA. After joining the University of Leicester in December 2017, I have been awarded a Seed Award from the Wellcome Trust and a King Abdullah University of Science and Technology (KAUST) collaborative research grant, to make use of Cryo-Electron Microscopy (Cryo-EM) to explore the architecture and function of DNA replication and repair machines. In collaboration with Prof. Samir Hamdan’s laboratory at KAUST, we have recently solved the near-atomic resolution Cryo-EM structure of the human Okazaki fragment processing complex, which includes the lagging strand DNA polymerase d, primed DNA, PCNA and flap endonuclease 1 (FEN1). This work shows for the first time the modular organization of a eukaryotic DNA polymerase and the molecular details of the interaction with its clamp, providing insights into the mechanisms of lagging strand replication and nick translation of Okazaki fragments.

Qualifications

  • M.Sc., University of Padua, Italy
  • Ph.D., International Centre for Genetic Engineering and Biotechnology, Italy

Publications

  1. Lancey C., Tehseen M., Takahashi M., Sobhy M.A., Ragan T.J., Crehuet R., Hamdan S.M.* and De Biasio A.* Cryo-EM structure of Pol k-DNA-PCNA holoenzyme and implications for polymerase switching in DNA lesion bypass” Preprint at https://www.biorxiv.org/content/10.1101/2020.07.10.196956v1
    *corresponding author
  2. Lancey C., Tehseen M., Raducanu V.S., Rashid F., Merino N., Ragan T.J., Savva C., Zaher M.S., Shirbini A., Blanco F.J., Hamdan S.M.* and De Biasio A.* (2020) “Structure of the processive human Pol d holoenzyme”, Nat. Commun. 11: 1109**
    *corresponding author
    ** Paper recommended by F1000Prime

  3. González-Magaña A., Ibáñez de Opakua A., Merino N., Monteiro H., Diercks T., Murciano-Calles J., Luque I., Bernadó P., Cordeiro T.N., De Biasio A., Blanco F.J. (2019) “Double monoubiquitination modifies the molecular recognition properties of p15PAF promoting binding to the reader module of Dnmt1”, ACS Chem. Biol. 18;14(10): 2315-2326
  4. Gonzalez-Magaña A., Ibáñez de Opakua A., Romano-Moreno M., Murciano-Calles J., Merino N., Luque I., Rojas A.L., Onesti S., Blanco F.J.* and De Biasio A.* (2019) “Molecular recognition of the p12 subunit of human polymerase δ by PCNA through an atypical PIP-box”, J. Biol. Chem. 294(11): 3947-3956 
    *corresponding author
  5. De March M., Barrera-Vilarmau S., Crespan E., Mentegari E., Merino N., Gonzalez-Magaña A., Romano-Moreno M., Maga G., Crehuet R., Onesti S., Blanco F.J. and De Biasio A.* (2018) “p15PAF binding to PCNA modulates the DNA sliding surface” Nucleic Acids Res. 46(18): 9816-9828. *corresponding author
  6. De Biasio A.*, Ibáñez de Opakua A., Bostock M.J., Nietlispach D., Diercks T.* and Blanco F.J.*(2018) "A generalized approach for NMR studies of lipid-protein interactions based on sparse fluorination of acyl chains" Chem. Commun. (Camb) 54(53):7306-7309.
    *corresponding author
  7. De March M. & De Biasio A. (2017) “The dark side of the ring: role of the DNA sliding surface of PCNA”, Crit. Rev. Biochem. Mol. Biol. Aug 17:1-11.
  8. De March M., Merino N., Barrera-Vilarmau S., Crehuet R., Onesti S.*, Blanco F.J.* and De Biasio A.* (2017) “Structural basis of human PCNA sliding on DNA” Nat. Commun. 7, 13935**
    *corresponding author
    ** this paper was reviewed in Yao N. and O'Donnell M. “DNA Replication: How
    Does a Sliding Clamp Slide?” (2017) Curr. Biol. 27(5):R174-R176
  9. Cordeiro T.N., Chen P., De Biasio A., Sibille N., Blanco F.J., Hub J.S., Creuhet R. and Bernadó P. (2017) “Disentangling polydispersity in the PCNA‒p15PAF complex, a disordered, transient and multivalent macromolecular assembly” Nucleic Acids Res. 45(3):1501-1515
  10. De Biasio A.*, Ibañez de Opakua A., Mortuza G., Molina A., Cordeiro T.N., Castillo F., Villate M., Merino N., Delgado S., Gil-Cartón D., Luque I., Diercks T., Bernadó P., Montoya G. and Blanco F.J.* (2015) “Structure of p15PAF‒PCNA complex and implications for clamp sliding during DNA replication and repair” Nat. Commun. 6:6439
  11. De Biasio A., Ibáñez de Opakua A., Cordeiro T.N., Villate M., Merino N., Sibille N., Lelli M., Diercks T., Bernadó P., Blanco F.J. (2014) “p15PAF is an intrinsically disordered protein with nonrandom structural preferences at sites of interaction with other proteins” Biophys. J. 106(4):865-74
  12. De Biasio A. and Blanco F.J. (2013) “Proliferating Cell Nuclear Antigen (PCNA) Structure and Interactions. Too Many Partners for One Dancer?”, Adv. Protein Chem. Struct. Biol. 91:1-36
  13. Kolyada A., De Biasio A. and Beglova N. (2013) “Identification of the binding site for fondaparinux on Beta2-glycoprotein I” Biochimica et Biophysica Acta 1834(10):2080-2088
  14. De Biasio A., Campos-Olivas R., Sánchez R., López-Alonso J.P., Pantoja-Uceda D., Merino N., Villate M., Martín-García J.M., Castillo F., Luque I., and Blanco F.J. (2012) “Proliferating Cell Nuclear Antigen (PCNA) interactions in solution studied by NMR”, PLoS ONE 7(11): e48390
  15. Nifoussi S.K., Vrana J.A., Domina A.M., De Biasio A., Gui J., Gregory M.A., Hann S.R., Craig R.W. (2012) “Thr 163 phosphorylation causes Mcl-1 stabilization when degradation Is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer”, PLoS One 7(10): e47060
  16. De Biasio A., Sánchez R., Prieto J., Campos-Olivas R., Blanco F.J. (2011) “Reduced stability and increased dynamics in the human proliferating cell nuclear antigen (PCNA) relative to the yeast homolog”, PLoS ONE 6(2): e16600
  17. Kolyada A., Lee C.J., De Biasio A. and Beglova N. (2010) “A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/Antibody complexes implicated in Antiphospholipid Syndrome”, PLoS One 5(12): e15345
  18. Beglov D., Lee C.J., De Biasio A., Kozakov D., Brenke R., Vajda S. and Beglova N. (2009) “Structural insights into recognition of beta2-glycoprotein I by the lipoprotein receptors”, Proteins 77(4):940-9
  19. Lee C.J., De Biasio A., Beglova N. (2010) “The mode of interaction between B2GPI and lipoprotein receptors suggests that the binding of B2GPI to the receptors and anionic phospholipids is mutually exclusive” Structure 18(3):366-76
  20. De Biasio A., Guarnaccia C., Popovic M., Uversky V.N., Pintar A. and Pongor S. (2008) “Prevalence of Intrinsic Disorder in the Intracellular Region of Human Single-Pass Type I Proteins: The Case of the Notch Ligand Delta-4” Journal of Proteome Research 7(6):2496-506
  21. Popovic M., De Biasio A., Pintar A. and Pongor S. (2007) “The intracellular region of the Notch ligand Jagged-1 gains partial structure upon binding to synthetic membranes”, FEBS Journal 274(20):5325- 36
  22. Pintar A., De Biasio A., Popovic M., Ivanova N. and Pongor S. (2007) “The intracellular region of Notch ligands: does the tail make the difference?” Biology Direct 2:19
  23. De Biasio A., Vrana J.A., Zhou P., Qian L., Bieszczad C.K., Braley K.E., Domina A.M., Weintraub S.J., Neveu J.M., Lane W.S. and Craig R.W. (2007) “N-terminal truncation of antiapoptotic MCL1, but not G2/M-induced phosphorylation, is associated with stabilization and abundant expression in tumor cells” Journal of Biological Chemistry 282(33):23919-36

Research

The genetic information is encoded in long chains of deoxyribonucleic acid (DNA) molecules packaged into chromosomes in the cell nucleus. Before dividing, cells need to accurately duplicate their DNA, to ensure that each daughter cell has an identical copy. Critical players in DNA replication are the so-called DNA clamps, ring-shaped proteins that slide on the DNA double helix and anchor the polymerases, the enzymes that replicate DNA, to the genomic template. Beside DNA replication, sliding clamps function in the DNA damage response and the maintenance of genome integrity. Due to their central role in cell proliferation, DNA clamps are an important hallmark of tumors, as well as potential drug targets for anti-cancer therapy.

Our aim is to unravel the molecular architecture of eukaryotic DNA replication complexes involving DNA sliding clamps, and to shed light on their inner workings. To tackle these composite, supramolecular assemblies we integrate structural (X-ray, NMR, Cryo-Electron Microscopy), biochemical and computational methods.

In our work, we have determined the structure of the human clamp PCNA bound to p15PAF, a modulator of the DNA damage tolerance pathway, revealing a unique mode of binding with functional implications. Our work has also provided a structural basis for the mechanism of PCNA sliding on DNA.

Our current research exploits the power of single-particle Cryo-EM to unravel the structure and mechanism of the human holoenzymes that replicate normal and damaged DNA. We have recently determined the Cryo-EM structure of the human Okazaki fragment processing complex, which includes the lagging strand DNA polymerase d, primed DNA, PCNA and flap endonuclease 1 (FEN1). We have also determined the structure of human Pol k-PCNA-DNA complex, the holoenzyme that replicates DNA through regions of damage.

> See my LISCB research page.

Supervision

A Postdoc position is available in my lab. - Link to follow when the advert goes live

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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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