Exploitation of pronounced cancer cell death upon dual loss of DNA end protection and nuclease restraint

DNA damage is a frequent occurrence in our cells, and we have evolved a range of elegant mechanisms to repair this damage. Cancer can develop when these mechanisms fail, or when the cell is forced to choose suboptimal forms of DNA repair that lead to mutations. 

In some cases, inherited defects in DNA repair genes can also represent a tumour vulnerability. For example, cancers with mutations in the BRCA1 gene are selectively targetable by the precision use of medicines called PARP inhibitors. This exploitation of cancer-specific genetic weaknesses is called synthetic lethality.

We have identified a novel type of synthetic lethality and have shown that cancer cells die upon losing a particular combination of DNA repair proteins. During DNA repair, DNA is digested by enzymes called nucleases, and this helps the cell choose which repair mechanism to use. Various cellular factors control DNA digestion – some proteins bind and protect DNA ends (53BP1, RIF1) while others restrain nucleases (MRNIP). We discovered that loss of DNA protection in combination with defective nuclease restraint leads to efficient cancer cell death. 

Our goal is to understand why loss of these fail-safes is lethal, and to exploit our findings to kill cancers – even those that have become resistant to normal treatments.