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.
We study the mechanism of enzymatic synthesis of novel DNA during replication. Priming DNA synthesis is especially challenging on the so-called lagging strand of the replication fork, due to the anti-parallel direction of the strands in the double helix. In parallel, we are interested in understanding the molecular mechanisms that control homologous recombination, a pathway of double-strand break repair that is essential for the smooth progression of the replication fork.
Lab members: Joseph Maman, Mairi Kilkenny, Neil Rzechorzek, Mike Longo, Aline Simon, Johanna Syrianen, Sandro Holzer, David Wirthensohn, Christopher Morton.
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 Jan 5. doi: 10.1038/nsmb2937. [Epub ahead of print]
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 Nov 25; 5:5506. doi:10.1038:ncomms6506.
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
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
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
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
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
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
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.
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
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