Molecular mechanisms of maintaining gentic stability in aging and in preventing cancer
Thomas Helleday, Dept. of Genetics Microbiology and Toxicology

Aging and Cancer are caused by genetic instability. Two critical pathways in maintaining genetic stability are Poly(ADP-ribose) polymerase (PARP-1) and homologous recombination (HR). Familial breast cancer is commonly caused by an inherited defect in one of the BRCA1 or BRCA2 alleles. During the course of life, the functional BRCA1 or BRCA2 gene can be lost in some cells to initiate the development of a tumour. However, a BRCA2 defect is lethal to the cell and will make it die. Therefore additional chances are required to make BRCA2 deficient cells viable, such as a mutation in p53. A p53 mutation is still not sufficient to make epithelial breast cells tumourogenic and additional mutations of tumour suppressors are required. We have also found that PARP-1 is critical to maintain genetic stability in BRCA2 deficient cells. AIM In this project we want to understand more about the link between HR and PARP-1 in maintaining genetic stability in aging and cancer. In this project we will identify tumour suppressors in breast epithelial cells that will allow these to become tumourogenic. Furthermore, we characterise the molecular function of these tumour suppressors, using a mammalian cell culture model system and molecular biology techniques see how they influence PARP-1 and HR activities. We will use a vast range of molecular and cellular biology techniques as well as biochemistry to determine the effects.

Recent publications: 1. Bryant, H.E., Schultz, N, Thomas, H.D., Parker, K.M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N.J., Helleday, T. (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase Nature, in press. 2. El-Khamisy, S.F., Saifi, G.M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J.R., Caldecott, K.W. (2005) Defective DNA Single-Strand Break Repair in Spinocerebellar Ataxia with Axonal Neuropathy-1, Nature, in press. 3. Sørensen, C.S., Hansen, L.T., Dziegielewski, J., Syljuåsen, R.G., Lundin, C., Bartek, J., Helleday, T. (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair, Nature Cell Biology, doi:10.1038/ncb1212. 4. Saleh-Gohari, N., Helleday, T. (2004) Strand invasion involving short tract gene conversion is specifically suppressed in BRCA2-deficient hamster cells Oncogene, 23(56), 9136-41. 5. Kumari, A., Schultz, N., Helleday, T. (2004) p53 protects from DNA double-strand breaks at stalled replication forks in mammalian cells, Oncogene, 23(13), 2320-2325.