Maintenance of Genome Stability

Steve's group focuses on understanding how cells detect, signal the presence of, and repair DNA damage.

The cells in our bodies are constantly exposed to radiation and chemicals that damage DNA. To protect them, cells have a system that detects DNA damage, signals that damage has occurred, and facilitates its repair. The process, known as the DNA damage response (DDR), is crucial for cell survival and guards against various diseases, including neurodegenerative disease and cancer.

The Maintenance of Genome Stability team are aiming to understand precisely how cells respond to DNA damage. Such research will provide new insights into human cell biology and human disease. Discovering how defects in the DNA damage response can lead to disease may lead to better diagnosis and treatment.

[Polo and Jackson 2011 Genes & Dev 25, 409-33.]


While much progress has been made in identifying DNA damage response proteins, much remains to be learned about the molecular and cellular functions that they control. Furthermore, the frequent reporting of new DDR proteins in the literature suggests that many others await identification.

To fully understand the DDR and establish how this knowledge might be applied medically, there is a need to define the full complement of DDR components and DDR regulators, and determine how they function. We are working with both yeast and mammalian cells to:

  • identify new DDR factors
  • define the functions of known DDR components
  • assess how the DDR is regulated
  • assess how the DDR is affected by chromatin structure.

We are also collaborating with clinicians and drug-discovery scientists to develop our findings to clinical applications.


Identifying DDR genes in specific chromatin contexts.

In order for DDR proteins to detect and repair damaged DNA, the DNA must be accessible. Until now, not much is known about how this occurs within the context of chromatin. We aim, in collaboration with groups at the Sanger Institute, to identify new genes that act locally at sites of DNA damage to modify chromatin.

Cell-based screening for new DDR components and regulators.

We are using microscope based siRNA screens to identify new DDR components in human cells and hope to collaborate with other scientists at the Sanger Institute to further develop such screening strategies.

Proteomic analyses to identify and characterise DDR proteins and their interactors.

We are constructing human cell lines expressing tandem-epitope tagged derivatives of select DDR proteins. These will be affinity-purified and analysed for interacting proteins. We will be collaborating with colleagues at the Sanger Institute in this work.

Identifying DDR deficiencies in human developmental disorders.

DDR defects can yield human syndromes with varying and diverse symptoms. For example, we recently identified mutations in the DDR protein CtIP that cause Seckel syndrome, a recessively inherited dwarfism disorder characterised by microcephaly. It is highly likely that mutations in other DDR proteins may be responsible for other rare developmental disorders for the genetic basis is not yet known. We will work other groups at the Sanger Institute to explore possible DDR defects in these rare disorders.


Our research is drawing on the expertise and resources of the Sanger Institute. For example, to analyse mutations induced by DNA damage in wild-type and DDR-defective yeast strains we are collaborating with the Experimental cancer genetics project and the Cancer Genome Project. In addition, we will be working closely with the Cancer Genome Project to identify and develop new, molecularly targeted cancer therapies.

Selected publications

  • Chemical inhibition of NAT10 corrects defects of laminopathic cells.

    Larrieu D, Britton S, Demir M, Rodriguez R and Jackson SP

    Science (New York, N.Y.) 2014;344;6183;527-32

  • A new method for high-resolution imaging of Ku foci to decipher mechanisms of DNA double-strand break repair.

    Britton S, Coates J and Jackson SP

    The Journal of cell biology 2013;202;3;579-95

  • KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling.

    Kaidi A and Jackson SP

    Nature 2013;498;7452;70-4

  • Regulation of DNA damage responses by ubiquitin and SUMO.

    Jackson SP and Durocher D

    Molecular cell 2013;49;5;795-807

  • RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair.

    Galanty Y, Belotserkovskaya R, Coates J and Jackson SP

    Genes & development 2012;26;11;1179-95

  • Small-molecule-induced DNA damage identifies alternative DNA structures in human genes.

    Rodriguez R, Miller KM, Forment JV, Bradshaw CR, Nikan M, Britton S, Oelschlaegel T, Xhemalce B, Balasubramanian S and Jackson SP

    Nature chemical biology 2012;8;3;301-10

  • Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair.

    Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Kzhyshkowska J, Dobner T, Taylor AM, Turnell AS, Stewart GS, Grand RJ and Jackson SP

    Molecular cell 2012;45;4;505-16

  • Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.

    Polo SE and Jackson SP

    Genes & development 2011;25;5;409-33

  • Human SIRT6 promotes DNA end resection through CtIP deacetylation.

    Kaidi A, Weinert BT, Choudhary C and Jackson SP

    Science (New York, N.Y.) 2010;329;5997;1348-53

  • Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.

    Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM and Jackson SP

    Nature 2009;462;7275;935-9

  • The DNA-damage response in human biology and disease.

    Jackson SP and Bartek J

    Nature 2009;461;7267;1071-8

  • CDK targets Sae2 to control DNA-end resection and homologous recombination.

    Huertas P, Cortés-Ledesma F, Sartori AA, Aguilera A and Jackson SP

    Nature 2008;455;7213;689-92

  • Human CtIP promotes DNA end resection.

    Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J and Jackson SP

    Nature 2007;450;7169;509-14

  • XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining.

    Ahnesorg P, Smith P and Jackson SP

    Cell 2006;124;2;301-13

  • MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.

    Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ and Jackson SP

    Cell 2005;123;7;1213-26

  • Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.

    Falck J, Coates J and Jackson SP

    Nature 2005;434;7033;605-11

  • A DNA damage checkpoint response in telomere-initiated senescence.

    d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP and Jackson SP

    Nature 2003;426;6963;194-8

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