The careless repair of damaged DNA can cause mutations and can result in cancer. Cell biologists from the Erasmus University in Rotterdam studied the repair of double strand breaks. Such breaks can for example arise following radiotherapy.
The researchers simulated radiotherapy by specifically damaging the DNA of mouse cells. Mouse cells in which the gene Rad54 was first inactivated, more often chose a careless means of repairing the damaged DNA. In normal mouse cells no more than 60% of the repairs are done in a careless manner, whereas in cells with an inactivated Rad54 gene this figure was about 80%.
The results show that the Rad54 gene is important for repairing breaks in a neat manner and for preventing mutations. The scientists hope that their findings combined with future research will lead to improvements in the treatment of cancer. In the meantime the researchers are examining patients who overreact to radiotherapy. The idea is that physicians could for example give milder radiotherapy to patients who lack the Rad54 gene.
In another experiment the cell biologists examined the repair of cross-links. This type of damage arises after chemotherapy with, for example, melphalan, mitomycin C or cisplatin. The researchers inactivated the Snm1 gene in mice. After this the mice were given a small quantity of mitomycin.
Mice with a inactivated Snm1 gene died at a lower dose of mitomycin than mice with an intact Snm1 gene. This was probably because the mice with a inactivated Snm1 could not adequately repair the cross-links. Future research in patients who strongly react to chemotherapy must demonstrate whether this also involves a disrupted Snm1 gene.
DNA breaks can be repaired in three ways. The neat manner, homologous recombination, restores the break by copying information from an intact DNA molecule to the broken DNA molecule. The careless manner is called "sticking" recombination. This repair mechanism comes into play when the same piece of DNA is present slightly further along the same DNA molecule. The cell removes the undamaged intermediate piece of DNA. This costs less time than the neat manner but carries the risk that information will be lost. In the third manner, which is the simplest and most careless, the ends around a break are simply stuck together.
The defence of the doctoral thesis will take place on 16 January 2002. Ms Huizenga-Dronkert's supervisors are Prof. R. Kanaar and Prof. J.H.J. Hoeijmakers.
The research was funded by the Netherlands Organisation for Scientific Research (NWO).