Steve Jackson PhD FRS FMedSci, Frederick James Quick Professor of Biology, Member of the Biochemistry Department. Steve is also an Associate Faculty Member of the Wellcome Trust Sanger Institute.
Maintenance of genome stability
Our work focuses on the DNA-damage response (DDR), which optimises cell survival and genome integrity by detecting DNA damage, signalling its presence and mediating its repair. As DDR defects are associated with neurodegenerative diseases, immunodeficiencies, premature ageing, infertility and cancer, our research might suggest new ways to alleviate such conditions.
Over the past year, we have obtained important new insights into DDR processes. For example, we have used super-resolution microscopy to visualise the spatial and temporal distribution of the DDR proteins BRCA1 and 53BP1, enhancing our understanding of how the activities of these factors are coordinated (1). In addition, we have identified human hnRNPUL proteins 1 and 2 as binding partners for the double-strand break (DSB) sensor complex MRN (MRE11-RAD50-NBS1), work that provides new insights into how cells respond to DSBs (2). Furthermore, this work together with proteomics-based studies that we carried out in collaboration with Dr C Choudhary (Denmark; 3) have highlighted crucial connections between RNA metabolism and DNA repair.
We have also continued to focus on how the DDR is controlled by protein post-translational modifications. For instance, we established how the SUMO targeted ubiquitin E3 ligase (STUBL) RNF4 promotes DSB repair, shedding new light on the molecular dynamics regulating DSB signalling and repair, and highlighting the interplay between ubiquitylation and SUMOylation (4). Finally, with Prof S Balasubramanian (Department of Chemistry), we used a synthetic small molecule that targets G-quadruplexes – four-stranded non-Watson-Crick DNA structures – to map the locations of these structures in the human genome, define how they impact on transcription, and show how they can be targeted to inhibit cancer cell growth (5).
• Chapman JR, Sossick AJ, Boulton SJ and Jackson SP (2012) BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J Cell Sci, 125, 3529-3534
• Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Kzhyshkowska J, Dobner T, Taylor AMR, Turnell AS, Stewart GS, Grand RJ and Jackson SP (2012) Regulation of DNA-End Resection by hnRNPU-like proteins promotes DNA double-strand break signalling and repair. Mol Cell, 45, 505-516
• Beli P, Lukashchuk N, Wagner SA, Weinert BT, Olsen JV, Baskcomb L, Mann M, Jackson SP and Choudhary C (2012) Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. Mol Cell, 46, 212-25
• Galanty Y, Belotserkovskaya R, Coates J and Jackson SP (2012) RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev, 26, 1179-95
• Rodriguez R, Miller KM, Forment JV, Bradshaw CR, Nikan M, Britton S, Oelschlaegel T, Xhemalce B, Balasubramanian S and Jackson SP (2012) Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol, 8, 301-10