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Professor Mark Sansom, Head of Department
Key role for newly identified sensor protein in DNA repair
DNA repair in action: DNA ligase encircles the double helix to repair a broken strand of DNA. (Wikimedia) (Click to enlarge)
Researchers in the department have identified a sensor protein for a specific type of DNA damage in the cell.
Martin Cohn's lab, in collaboration with colleagues at Harvard Medical School, describe the findings in a recent paper in Cell Reports (1).
The discovery gives insight into the Fanconi anemia (FA) pathway, which cells use to repair toxic DNA interstrand crosslinks. In the longer term, it could have clinical relevance by helping to identify molecular targets for personalised cancer treatments.
Interstrand crosslinks (ICLs) are one of the many types of DNA lesions that cells must respond to and repair. The FA pathway carries out repair of ICLs via steps that include nucleotide excision repair, translesion synthesis and homologous recombination.
Researchers have identified 17 genes that work together along the FA pathway. This includes genes such as BRCA1 and BRCA2 that are involved in other DNA repair pathways. A defect in one of the 17 genes can give rise to Fanconi anaemia, a recessive cancer predisposition and developmental syndrome.
As Eric Liang, a third-year DPhil student in the Cohn lab who carried out much of the work explains, a protein called FANCD2 is central to the repair. 'FANCD2 is a core protein that is known to be recruited to the damage site, and other proteins follow afterwards. If FANCD2 is absent, then the pathway is completely shut off.'
The proteins that specifically recognise ICLs, however, are unknown. So Dr Cohn, a Royal Society University Research Fellow, and his former DPhil student Jamie Zhan devised an assay that would help to identify this.
They extracted nuclear protein from cells that has been treated with compounds to activate the ICL repair pathways. Then, adding biotin-labelled DNA substrates with either no ICL or an ICL, they pulled down proteins in the extract that interacted with these two structurally distinct DNA molecules.