Introduction

Research Groups

Select Research Group Head Prof. Sir Tom Blundell Prof. Kevin Brindle Dr Bill Broadhurst Dr Guy Brown Dr Mark Carrington Prof. Paul Dupree Prof. Gerard Evan - Head of Dept Prof. Richard Farndale Dr Giorgio Favrin Dr Jenny Gallop Dr Nick Gay Dr Andrew Grace Dr Jules Griffin Dr Brian Hendrich Dr Andrew Hesketh Dr Robin Hesketh Dr Matt Higgins Dr Florian Hollfelder Dr Hee-Jeon Hong Prof. Chris Howe Dr Marko Hyvonen Prof. Steve Jackson Dr Tony Jackson Prof. Richard Jackson Prof. Ernest Laue Prof. Peter Leadlay Dr Kathryn Lilley Dr Karen Lipkow Dr Rick Livesey Prof. Ben Luisi Dr Sarah Lummis Dr Juan Mata Dr John McCafferty Prof. Jim Metcalfe Dr Masanori Mishima Dr Eric Miska Dr Tom Monie Dr Helen Mott Dr Natasha Murzina Dr Daniel Nietlispach Dr Darerca Owen Prof. Steve Oliver Dr Luca Pellegrini Dr Markus Ralser Dr Nick Robinson Prof. George Salmond Dr Deirdre Scadden Dr José Silva Prof. Austin Smith Prof. Chris Smith Dr Nancy Standart Prof. Dame Jean Thomas Dr Aviva Tolkovsky Dr Martin Welch Dr Joyce Wong Dr Nianshu Zhang

Service & Research Support Facilities

Select by Subject or Manager DNA Sequencing Facility . . . . . Mr John Lester _______________________________ Quantitative Proteomics . . . . . Dr Kathryn Lilley _______________________________ Proteomics Core Services . . . . . Dr Mike Deery _______________________________ Protein & Nucleic Acid Chemistry . . . . . Dr Len Packman _______________________________ Metabolomics . . . . . Dr Jules Griffin _______________________________ Baculovirus Facility . . . . . Dr Darerca Owen _______________________________ Biophysics Facility . . . . . Dr Katherine Stott _______________________________ Crystallographic X-ray Facility . . . . . Dr Dima Chirgadze _______________________________ NMR spectroscopy . . . . . Dr Daniel Nietlispach _______________________________ Fermentation Facility . . . . . Dr Nianshu Zhang _______________________________ Bioinformatics & Computational Biology Services . . . . . Dr Jenny Barna _______________________________ Computer & IT Support . . . . . Dr Erik Timmers _______________________________

Past members last known active weblink

Select past member of Department Dr Stephen Bell Prof. Jonathan Blackburn Dr David Brown Dr Pak-Lee Chau Dr Hal Dixon (deceased) Dr Jessica Downs Prof. David Ellar Dr Paul Kemp Dr Simon Lovell Dr Kenji Mizuguchi Dr Massimo Paoli Prof. Richard Perham Dr Peter Reynolds Dr Philip Rubery Dr Gerry Smith Dr Margaret Sunde Prof. Jamie Vandenberg Dr Kira Weissman

Reset Menus

Visit Jackson group web site and Gurdon Institute page

Maintenance of genome stability

Research Groupings: Cancer | Structural and molecular cell biology

Our work focuses on the DNA-damage response (DDR): the set of events that optimises cell survival by detecting DNA damage, signalling its presence and mediating its repair. The importance of the DDR is underscored by defects in it being associated with various pathologies, including neurodegenerative disease, immunodeficiency, premature ageing, infertility and cancer.

Larger image in new window

Figure 1.  Common DNA-damage recruitment and activation mechanisms for ATM, DNA-PKcs and ATR. These proteins are recruited and activated at sites of damage through interactions with their partner proteins – NBS1 (part of the MRE11-RAD50-NBS1 (MRN) complex), Ku80 and ATRIP – to bring about DDR signalling or repair, as indicated. Model derived from Falck J, Coates J, Jackson SP. (2005). Nature 434:605-611.

By working with both yeast and human cells, we are identifying new DDR factors, defining the functions of known DDR components, assessing how the DDR is affected by chromatin structure, and learning how DDR events are regulated. For example, we recently discovered that – like the yeast Sae2 protein – the human CtIP protein functionally interacts with the MRN complex to promote processing (resection) of DNA double-strand breaks (DSBs) to generate single-stranded DNA that activates the DDR kinase ATR and triggers DNA repair by homologous recombination. Moreover, we found that CtIP and Sae2 share a highly conserved cyclin-dependent kinase (CDK) phosphorylation site, and discovered that its phosphorylation facilitates resection, thus promoting ATR signalling and HR in S/G2 but not G0/G1. Furthermore, we recently discovered that the yeast Sgs1 helicase and its human counterpart BLM (mutated in cancer-predisposed Bloom syndrome patients) promote resection, HR and ATR signalling by a pathway that is distinct from that mediated by MRN and Exonuclease I. Another highlight over the past year has been our demonstration that phosphorylation-dependent interactions between MRN and the DDR-mediator protein MDC1 are required for the association of MRN with chromatin flanking DSB sites. Our current work is geared towards further defining the mechanisms and biological functions of these and other DDR events.

Larger image in new window		Larger image in new window
Figure 2.   Cell-cycle coordination of DSB signalling and repair.  In G1, cells carry out little DSB resection, leading to activation of ATM-dependent signalling and DSB repair by non-homologous end-joining (NHEJ).  In S and G2 cells, ATM signalling also occurs but in these circumstances, CtIP – in conjunction with the MRE11-RAD50-NBS1 (MRN) complex – promotes DSB processing to generate single-stranded DNA that triggers ATR activation and leads to repair by homologous recombination (HR).  Our recent work has shown that CDK phosphorylation of CtIP and its yeast homologue, Sae2, is required for ssDNA formation and HR.		Figure 3: MDC1-dependent retention of the MRN complex on γH2AX-coupled chromatin spanning DSBs. The Casein Kinase 2 (CK2) phosphorylated SDTD repeat-motifs of MDC1 are bound by the FHA-domain of NBS1, allowing the MRN complex to be recruited to damaged chromatin when MDC1 binds ATM-phosphorylated histone H2AX (γH2AX). The resulting co-localisation of MDC1 and NBS1 can be visualised along tracts of laser-induced DNA DSBs (lower left panels), yet this co-localisation is compromised in human cells expressing an MDC1 mutant lacking the SDTD motifs, resulting in an impaired NBS1 recruitment (lower right panels).

Lab members
Linda Baskcomb, Rimma Belotserkovskaya, Melanie Blasius, Ross Chapman, Julia Coates, Kate Dry, Sonja Flott, Josep Forment, Yaron Galanty, Simona Giunta, Ilaria Guerini, Jeanine Harrigan, Pablo Huertas, Abderrahmane Kaidi, Helen Kirkman, Natalia Lukashchuk, Kyle Miller, Tobias Oelschlägel, Sophie Polo, Helen Reed, Jorrit Tjeertes

References