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Luca Pellegrini

Macromolecular mechanisms of genome duplication and stability

Please visit our lab website for further information.


 

The faithful inheritance of genetic information is essential to cellular life. Successful transmission of the genetic material requires the accurate replication of the genome and the repair of any DNA lesion that might block replication or alter the encoded message. Failure of the complex molecular systems that preserve the integrity of our DNA is a major contributing factor in human disease.

Our research aims to define structural and functional properties of proteins and protein complexes responsible for the maintenance and replication of our genome.  Our experimental approach involves the reconstitution in vitro of the biological system under investigation, which can then be subject to biochemical and biophysical analysis. We work on processes that pertain to both DNA repair and replication. Please see our publication list below for more information.

Our research is funded by the Wellcome Trust and the Medical Research Council.

Lab members: Joseph Maman, Mairi Kilkenny, Neil Rzechorzek, Laura Radu, Daniel Bollschweiler, Christopher Morton, Aji Jatikusumo, Yue Zhang.

Enquiries from talented and motivated students wishing to pursue a PhD in our lab are always welcome.


Publications:

2017

Wu Y, Villa F, Maman J, Lau YH, Dobnikar L, Simon AC, Labib K, Spring DR, Pellegrini L. Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design. Angew Chem Int Ed Engl. 2017 56:12866-12872. PubMed PMID: 28815832

Kolinjivadi AM, Sannino V, De Antoni A, Zadorozhny K, Kilkenny M, Técher H, Baldi G, Shen R, Ciccia A, Pellegrini L, Krejci L, Costanzo V. Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments. Mol Cell. 2017 67:867-881 PubMed PMID: 28757209

Pellegrini L. Structural insights into Cdc45 function: was there a nuclease at the heart of the ancestral replisome? Biophys Chem. 225:10-14. PubMed PMID: 27919598

Holzer S, Degliesposti G, Kilkenny ML, Maslen SL, Matak-Vinkovíc D, Skehel M, Pellegrini L. Crystal structure of the N-terminal domain of human Timeless and its interaction with Tipin. Nucleic Acids Res. 2017 45:5555-5563. PubMed PMID: 28334766

Syrjänen JL, Heller I, Candelli A, Davies OR, Peterman EJ, Wuite GJ, Pellegrini L. Single-molecule observation of DNA compaction by meiotic protein SYCP3. Elife. 2017 Mar 13;6. pii: e22582. doi: 10.7554/eLife.22582. PubMed PMID: 28287952

2016

Pellegrini L, Costa A. New Insights into the Mechanism of DNA Duplication by the Eukaryotic Replisome. Trends Biochem Sci. 2016 41:859-71. doi: 10.1016/j.tibs.2016.07.011. PubMed PMID: 27555051

Villa F, Simon AC, Ortiz Bazan MA, Kilkenny ML, Wirthensohn D, Wightman M, Matak-Vinkovíc D, Pellegrini L, Labib K. Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase. Mol Cell. 2016 63:385-96. PMID: 27397685.  

Simon AC, Sannino V, Costanzo V, Pellegrini L. Structure of human Cdc45 and implications for CMG helicase function. Nat Commun. 2016 7:11638. PubMed PMID: 27189187; PubMed Central PMCID: PMC4873980.

2015

Davies OR, Forment JV, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L. CtIP tetramer assembly is required for DNA-end resection and repair. Nat Struct Mol Biol. 2015 22:150-7.

2014

Rzechorzek NJ, Blackwood JK, Bray SM, Maman JD, Pellegrini L, Robinson NP. Structure of the hexameric HerA ATPase reveals a mechanism of translocation-coupled DNA-end processing in archaea. Nat Commun. 2014 5:5506.

Syrjanen JL, Pellegrini L, Davies OR. A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife 2014 Jun 20:e02963. doi: 10.7554/eLife.02963.

Simon AC, Zhou JC, Perera RL, van Deursen F, Evrin C, Ivanova ME, Kilkenny ML, Renault L, Kjaer S, Matak-Vinković D, Labib K, Costa A, Pellegrini L. A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome. Nature 2014 510 293-7

2013

Kilkenny ML, Longo MA, Perera RL, Pellegrini L. Structures of human primase reveal design of nucleotide elongation site and Pol α tethering. PNAS 2013 110 15961-6.

Perera RL, Torella R, Klinge S, Kilkenny ML, Maman JD, Pellegrini L. Mechanism for priming DNA synthesis by yeast DNA Polymerase α. eLife 2013;2:00482 

2012

Davies OR, Maman JD, Pellegrini L. Structural analysis of the human SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly. Open Biol. 2012 2 120099

Kilkenny ML, De Piccoli G, Perera RL, Labib K, Pellegrini L. A conserved motif in the C-terminal tail of DNA polymerase α tethers primase to the eukaryotic replisome. J Biol Chem. 2012 287 23740-7

Blackwood JK, Rzechorzek NJ, Abrams AS, Maman JD, Pellegrini L, Robinson NP. Structural and functional insights into DNA-end processing by the archaeal HerA helicase-NurA nuclease complex. Nucleic Acids Res. 2012 40 3183-96

2011

Núñez-Ramírez R, Klinge S, Sauguet L, Melero R, Recuero-Checa MA, Kilkenny M, Perera RL, García-Alvarez B, Hall RJ, Nogales E, Pellegrini L, Llorca O. Flexible tethering of primase and DNA Pol α in the eukaryotic primosome. Nucleic Acids Res. 2011 39 8187-99

2010

Sauguet L, Klinge S, Perera RL, Maman JD, Pellegrini L. Shared active site architecture between the large subunit of eukaryotic primase and DNA photolyase. PLoS One 2010 5 e10083

2009

Klinge S, Núñez-Ramírez R, Llorca O, Pellegrini L. 3D architecture of DNA Pol α reveals the functional core of multi-subunit replicative polymerases. EMBO J. 2009 28 1978-87.

2008

Ragone S, Maman JD, Furnham N, Pellegrini L. Structural basis for inhibition of homologous recombination by the RecX protein. EMBO J. 2008 27 2259-69

2007

Klinge S, Hirst J, Maman JD, Krude T, Pellegrini L. An iron-sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. Nat Struct Mol Biol. 2007 14 875-7

Davies OR, Pellegrini L. Interaction with the BRCA2 C-terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nat Struct Mol Biol 2007 14:475-83 PubMed PMID:17515903