A double-edged sword Homologous recombination in genome maintenance and cancer treatment

Our DNA is constantly exposed to endogenous and exogenous factors, including by-products of metabolic processes, chemical compounds, ionizing radiation and ultraviolet light, that threaten its integrity. To restore the various types of resulting DNA damage, cells evolved dedicated repair mechanisms. Double-strand breaks (DSBs) are among the most dangerous DNA lesions and can be repaired by two major DSB repair pathways, called homologous recombination (HR) and non-homologous end joining (NHEJ). Our experiments showed that HR is active in various murine tissues and tumors in vivo and decreases with age. Intriguingly, our results also showed that in vitro not only DSBs, but also nicks can trigger HR. Although mechanisms driving nick-induced HR partially overlap with the classical HR, we concluded that it is a bona-fide pathway for nick repair.
DNA repair mechanisms shield cancer cells from the cytotoxic effects of anticancer therapies. Hyperthermia (elevated temperature) is a clinically applied treatment that disrupts various DNA repair pathways, including HR, and can therefore sensitize cancer cells to radio- and chemotherapy. We found that hyperthermia treatment outcomes can be significantly improved by addition of small molecule inhibitors of PARP-1 or HSP90, paving the way for in vivo studies and future clinical trials.
In conclusion, this thesis portrays HR as a double-edged sword in cellular metabolism of DNA breaks. On the one hand, HR is essential in genome maintenance in healthy cells. On the other hand, interfering with HR can improve the outcomes of cancer therapies that rely on DNA damaging agents.