SupDSB · Mapping genetic suppression interaction networks in DNA break repair disorders

Mapping genetic suppression interaction networks in DNA break repair disorders

Every time a cell divides it must copy its DNA, and during this process the DNA molecule is constantly exposed to damage. The most dangerous form of damage is a "double-strand break", where the DNA is cut clean through. If such breaks are not mended, cells accumulate genetic errors, become unstable and die. To survive, cells rely on specialized repair pathways. Two proteins, BRCA1 and BRCA2, are central players in one such pathway. When they are missing, healthy cells normally cannot survive. Intriguingly, the very same proteins, when mutated, are associated with tumorigenic potential: people who inherit a faulty BRCA1 or BRCA2 gene face greatly increased risks of breast, ovarian, prostate and pancreatic cancer. So how can cancer cells lose BRCA1 or BRCA2 and still grow aggressively, when healthy cells die without them? The answer is that cancer cells adapt by acquiring compensatory genetic changes that let them tolerate the loss of BRCA proteins. Until now, most research studies have focused on tumor cells that adapted long ago, making it very hard to identify which changes were actually responsible for survival. SupDSB set out to catch adaptation to BRCA-loss as it happens. The core idea was to begin with healthy cells, switch off BRCA1 or BRCA2 suddenly, and then search the whole genome for the helper changes that allow cells to survive. Such survival-enabling changes are known as genetic suppressors. The objectives were threefold: first, to build cell systems in which BRCA1 or BRCA2 can be removed within hours and on demand; second, to test every gene in the genome to find those whose loss rescues - or worsens - survival when BRCA1 or BRCA2 is gone; and third, to connect these laboratory findings to real patient data, in order to judge their relevance for diagnosis and treatment. Results obtained by SupDSB could have implications for precision medicine. Understanding the routes cells follow to survive BRCA loss should help predict who is most at risk, anticipate how tumors become resistant to therapy, and design treatments tailored to each tumor's exact genetic make-up. Because BRCA-related cancers are common and carry a heavy human and economic cost, the potential benefit to society is substantial.

Data: CORDIS, © European Union