Unravelling the workings of BRCA2
20 July 2009
Researchers at the MRC Cancer Cell Unit in Cambridge have identified a new way in which the BRCA2 protein functions during the DNA repair process.
The BRCA2 gene encodes a protein that plays a crucial role in repairing damage to DNA, and thus protects cells from mutations that might induce cancer. People who inherit defective copies of this gene have an increased risk of developing breast, ovarian and prostate cancer, as the BRCA2 protein is not able to undertake its normal function. DNA repair occurs via a mechanism known as homologous DNA recombination (HDR). During HDR, breaks in the DNA double helix are repaired via a process of recombination, or exchange, with an undamaged section of identical DNA. This can occur because most cells contain two copies of each chromosome.
The HDR process has three main steps; firstly additional sections of DNA around the break are removed to leave single strands, one of these strands then ‘invades’ the appropriate region of the undamaged chromosome and forms a structure that allows DNA recombination to take place, and finally the gaps on each chromosome are filled-in to return both to their normal, undamaged, double-stranded state.
A key enzyme involved in this process is RAD51, and its actions are controlled by BRCA2. However exactly how BRCA2 influences HDR has previously been unknown. Although RAD51 can bind to both single and double strands of DNA, the Cambridge team have demonstrated that BRCA2 promotes RAD51 binding to single-stranded DNA in order to mediate recombination. They also found that its binding to double-stranded DNA is inhibited by BRCA2. This is beneficial to the cell as these opposing effects work together to ensure that the steps involved in HDR take place in the correct sequence, and that DNA damage is efficiently repaired.
Lead author Professor Ashok Venkitaraman commented:
“We have identified a new way in which BRCA2 works to prevent cancer by acting as a ‘guardian’ of the human genome. This work not only helps us to improve our understanding of how BRCA2 functions within cells, but in the future could also suggest new approaches to developing treatments for cancer.”
Original research paper: 'The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange' appears in the current issue of Proceedings of the National Academy of Sciences USA and develops work published by the MRC team in collaboration with Professor Stephen Kowalczykowski, University of California (The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC. Cell. 2009 Mar 20;136(6):1032-43).
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