Jackson Group
Maintenance of genome stability
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This page is maintained as a historical record and is no longer being updated.
Steve Jackson was a member of Associate Faculty at the Wellcome Sanger Institute until 2017. This page is being maintained as a historical record of work his group carried out at the Sanger Institute is no longer being updated.
Steve Jackson's research focuses on understanding how cells detect and repair DNA damage via the activities of the 'DNA-damage response' (DDR). The importance of the DDR for maintaining good health is shown by the diseases that are associated with the alteration or loss of these activities; including neurodegenerative disease, immunodeficiency, premature ageing, infertility and cancer.
Steve’s research 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 at the Wellcome Sanger Institute aimed to understand precisely how cells respond to DNA damage. Such research provided new insights into human cell biology and human disease. Discovering how defects in the DNA damage response can lead to disease could lead to better diagnosis and treatment.
Background
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 worked 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 also collaborated with clinicians and drug-discovery scientists to develop our findings to clinical applications.
Key areas of research
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. In collaboration with groups at the Sanger Institute, we sought 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 used microscope-based siRNA screens to identify new DDR components in human cells and sought 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 constructed human cell lines expressing tandem-epitope tagged derivatives of select DDR proteins. These will be affinity-purified and analysed for interacting proteins. We collaborated 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 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 worked with other groups at the Sanger Institute to explore possible DDR defects in these rare disorders.
