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Engineering zinc fingers to target cancer hub genes

Objective

For the last ten years, protein engineering technologies have been developed to make zinc finger peptides to recognise a wide variety of user-defined DNA sequences. This has enabled the construction of synthetic transcription factors that can upregulate or repress target genes at will. More recently, synthetic zinc fingers have been linked to nucleases to direct double stranded breaks at desired loci within genomes. These breaks increase the efficiency of homologous recombination so that, by providing an exogenous repair sequence, it is possible to repair or mutate endogenous genes. Although zinc finger engineering has reached a state of maturity, there are very few groups in the world who have the technical know-how to adopt this technology, and this has delayed general uptake. We will use the expertise we have developed, in both zinc finger engineering and gene repair, to construct zinc finger proteins to recognise some of the most highly-connected (and widely-studied) genes in biology. This will serve as a toolkit for the research community to target hub genes and either mutate or repair them. As a starting point we propose to target the following hub genes: TBP (TATA-binding protein), p53, p300, RXR, pRB, RelA, c-jun, c-myc, and c-fos. These genes are the most connected hubs in the human transcription factor network (TRANSFAC 8.2 database) and their mutants are associated with a variety of diseases. We will engineer and characterise zinc finger proteins that recognise these DNA sequences in vitro and induce gene repair in vivo. For example, this will allow cancer cell lines to have particular oncogenes repaired or mutated, within the context of all the other mutations that have been accrued during the process of oncogenesis. This will help to characterise the contribution of network nodes and hubs to the observed phenotypes. Ultimately, some of the gene repair peptides we create will have therapeutic potential, as well as providing tools for systems biology.

Field of science

  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 258 527,71
Principal investigator
Mark Isalan (Dr.)
Administrative Contact
Brooke Alasya (Ms.)

Beneficiaries (2)

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
United Kingdom
EU contribution
€ 258 527,71
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
Activity type
Higher or Secondary Education Establishments
Principal investigator
Mark Isalan (Dr.)
Administrative Contact
Brooke Alasya (Ms.)
FUNDACIO CENTRE DE REGULACIO GENOMICA

Participation ended

Spain
EU contribution
€ 1 069 161,29
Address
Carrer Doctor Aiguader 88
08003 Barcelona
Activity type
Research Organisations
Administrative Contact
Stefan Pönisch (Mr.)