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’s being associated with various pathologies, including neurodegenerative disease, immunodeficiency, premature ageing, infertility and cancer (1).
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. Much of this work is focused on how the DDR is controlled by protein post-translational modifications (PTMs; 2). For example, we have established that the mammalian SUMO E3 ligases PIAS1 and PIAS4 accumulate at DSB sites and promote cellular responses to DNA double strand breaks (DSBs) by mediating SUMOylation of various DDR factors (3). Furthermore, we recently discovered that the histone deacetylase enzymes HDAC1 and HDAC2 accumulate at DSB sites to facilitate repair by non-homologous end-joining (4). Our current work is geared towards further defining the mechanisms of the DDR particularly within the context of chromatin, and the role that PTMs have in controlling this key biological response.
Lab members: Gabriel Balmus, Ana Barros, Linda Baskcomb, Rimma Belotserkovskaya, Serene Bologna, Will Chiang, Julia Coates, Muku Demir, Harveer Dev, Kate Dry, Josep Forment, Yaron Galanty, Nicola Geisler, Mareike Herzog, Delphine Larrieu, Donna Lowe, Francisco Muñoz-Martinez, Domenic Pilger, Fabio Puddu, Helen Reed, Israel Salguero, Matylda Sczaniecka-Clift, Sasha Selivanova, Rohan Sivapalan, Siyue Wang, Paul Wijnhoven
1. Chiang TW, le Sage C, Larrieu D, Demir M, Jackson SP. (2016) CRISPR-Cas9(D10A) nickase-based genotypic and phenotypic screening to enhance genome editing. Scientific Reports 6, 24356.
2. Schmidt CK, Galanty Y^, Sczaniecka-Clift M, Coates J, Jhujh S, Demir M, Cornwell M, Beli P, Jackson SP^. (2015) Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. Nature Cell Biology 17, 1458-1470. ^Co-corresponding authors
3. Wijnhoven P, Konietzny R, Blackford AN, Travers J, Kessler BM, Nishi R, Jackson SP. (2015) USP4 auto-deubiquitylation promotes homologous recombination. Molecular Cell 60, 362-373.
4. Puddu F*, Oelschlaegel T*, Guerini I, Geisler NJ, Niu H, Herzog M, Salguero I, Ochoa-Montaño B, Viré E, Sung P, Adams DJ, Keane TM and Jackson SP. (2015) Synthetic viability genomic screening defines Sae2 function in DNA repair. EMBO Journal 34, 1509-22. *These authors contributed equally to this work.
5. Ochi T*, Blackford AN*, Coates J, Jhujh S, Mehmood S, Tamura N, Travers J, Wu Q, Draviam VM, Robinson CV, Blundell TL^, Jackson SP^ (2015) PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185-188. *These authors contributed equally to this work. ^Co-corresponding authors.
6. Davies OR*, Forment JV*, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP^, Pellegrini L^. (2015) CtIP tetramer assembly is required for DNA-end resection and repair. Nature Structural and Molecular Biology 22, 150-157. *These authors contributed equally to this work. ^Co-corresponding authors.
7. Nishi R, Wijnhoven P, le Sage C, Tjeertes J, Galanty Y, Forment JV, Clague MJ, Urbé S, Jackson SP. (2014) Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nature Cell Biology 16, 1016-1026.
8. Larrieu D, Britton S, Demir M, Rodriguez R, Jackson SP. (2014) Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science 344, 527-532.
9. Kaidi A, Jackson SP. (2013) KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling. Nature 498, 70-74.
10. Jackson SP, Durocher D. (2013) Regulation of DNA Damage Responses by Ubiquitin and SUMO. Mol. Cell 49, 795-807.
11. Galanty Y, Belotserkovskaya R, Coates J, Jackson SP. (2012) RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev. 26, 1179-95.
12. Rodriguez R, Miller KM, Forment JV, Bradshaw CR, Nikan M, Britton S, Oelschlaegel T, Xhemalce B, Balasubramanian S^, Jackson SP^ (2012) Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol. 8, 301-310 ^Co-corresponding authors
13. Kaidi A, Weinert BT, Choudhary C, Jackson SP. (2010) Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348-1353.
14. Jackson SP and Bartek J. (2009) The DNA damage response in human biology and disease. Nature 461, 1071-1078.
15. Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP. (2009) Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935-9.
16. Lloyd J*, Chapman JR*, Clapperton JA, Haire LF, Hartsuiker E, Li J, Carr AM, Jackson SP^, Smerdon SJ^. (2009) A supramodular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA damage. Cell 139, 100-11. *These authors contributed equally to this work. ^Co-corresponding authors.
17. Huertas P, Cortés-Ledesma F, Sartori AA, Aguilera A, Jackson SP. (2008) CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455: 689-692.