Our work focuses on the DNA-damage response (DDR): the set of events that optimises cell survival and genomic integrity 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, developmental defects, premature ageing, infertility and cancer. Indeed, we recently identified mutations in the DDR protein CtIP that cause Seckel syndrome, a recessively inherited dwarfism disorder characterised by microcephaly, and a related disease called Jawad syndrome (1).

For many years, we have been studying how protein phosphorylation controls the DDR.We have now carried out phospho-proteomic screens in collaboration with Dr. Chunaram Choudhary (Copenhagen, Denmark), enabling us to identify novel substrates of the cell-cycle checkpoint kinase Chk1 (2). In addition, we identified a DNA-damage dependent phosphorylation site on the key homologous recombination protein Rad51 that controls Rad51 function (3). Furthermore, we have studied how DNA damage arises in the absence of Chk1 activity, showing that this is mediated by the endonuclease Mus81/Eme1 (4). Another recent highlight has been our data showing how DNA replication stress leads to the formation of chromosomal fragile sites in G1 phase of the next cell cycle (5).This work has thus helped our understanding of how fragile sites arise and contribute to cancer and other diseases.

In addition, our studies have led to new therapeutic opportunities.To exploit these, with the assistance of Cancer Research Technology and Cambridge University, Steve Jackson founded MISSION Therapeutics whose aim is to translate new molecular understandings of human cell biology into drugs that will markedly improve the management of life-threatening diseases, particularly cancer.

Protein dynamics to and from sites of DNA breaks. DNA damage checkpoint and repair factors and modulators of chromatin organization are recruited (green arrows) to DNA breaks (SSB and DSB), while transcription machineries are excluded (red arrows), and the dynamics of structural chromatin components operate in both directions (orange arrows). HR, homologous recombination; NHEJ, non-homologous end joining.Taken from Polo SE and Jackson SP (2011) Dynamics of DNA damage response proteins at DNA breaks: A focus on protein modifications. Genes Dev 25, 409-433

Plain English:
The cells in our bodies are constantly being exposed to agents that damage our DNA, such as sunlight, or chemicals, in for example cigarette smoke, and also agents that occur naturally as part of normal cell metabolism. Cells have evolved a complex system, termed the DNA damage response (DDR) that detects DNA damage, signals its presence to the cell and sets about repairing this damage. The DDR is crucial for cell survival and to guard against cancer. In the Jackson lab we are trying to understand how cells respond when their DNA is damaged, in particular how proteins signal and repair DNA double strand breaks. Our aims are to: identify important DDR-proteins; determine how these proteins function; see how DDR events are affected by chromatin structure; and understand how the DDR impinges on diverse cellular events. It is hoped that, together with the work of others, such research will indicate how defects in the DNA damage response can lead to diseases such as cancer; neurodegenerative diseases and premature aging, and how such diseases might be better diagnosed and treated.

Selected publications:

• Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ, Jackson SP and Børglum AD (2011) CtIP mutations cause Seckel and Jawad syndromes. PLoS Genetics 7, e1002310 (1)

• Blasius M, Forment JV,Thakkar N,Wagner SA, Choudhary C and Jackson SP (2011) A phospho- proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol 12(8), R78 (2)

• Flott S, Kwon Y, Pigli YZ, Rice PA, Sung P and Jackson SP (2011) Regulation of Rad51 function by phosphorylation. EMBO Rep 12, 833-9 (3)

• Forment JV, Blasius M, Guerini I and Jackson SP (2011) Structure-Specific DNA Endonuclease Mus81/Eme1 Generates DNA Damage Caused by Chk1 Inactivation. PLoS ONE 6, e23517 (4)

• Harrigan JA, Belotserkovskaya R, Coates J, Dimitrova DS, Polo SE, Bradshaw CR, Fraser P and Jackson SP (2011) Replication stress induces 53BP1-containing OPT domains in G1 cells. J Cell Biol 193, 97-108 (5)

53BP1 (green) accumulates in nuclear bodies in a subset of G1 cells. Cyclin A positive cells (red) are in S/G2 phase of the cell cycle. Scale bar, 30 μm.

Schematic genetic map of chromosome 18 with the SCKL2 and Jawad loci, defined by homozygous chromosomal segments in affected consanguineous families.The CtIP gene spans 93 kb of genomic sequence covering 19 exons (vertical bars), of which 18 are coding. Red dots indicate positions
of mutations and point to sequence electropherograms of homo- and heterozygous carriers and corresponding wild-type sequence.