Regulation of chemosensitivity by the novel daughter strand gap suppressor MRNIP

All cells - even cancer cells - must copy their DNA if they are to divide, via a process called DNA 'replication' during which the genetic material is vulnerable to breakage, which in turn leads to cell death. Cancer cell killing is desirable, and therefore many chemotherapies work by targeting DNA replication to induce DNA breaks. Some cancers contain mutations in genes that function in DNA break repair, and these mutations render them sensitive to certain therapies. For example, the tumour suppressor genes BRCA1 and BRCA2 promote cancer cell survival by preventing the formation of toxic gaps in the DNA following chemotherapy treatment, and by helping repair therapy-induced DNA breaks. Patients with BRCA mutations often thus respond well to traditional chemotherapies like Cisplatin and the more advanced 'precision' medicine Olaparib.

We discovered MRNIP - a novel cellular factor that acts in a similar way to the BRCA genes, and which we have found also suppresses DNA gaps in Cisplatin and Olaparib-treated cancer cells. We have used a technique called CRISPR to delete the MRNIP gene, and discovered that cells lacking MRNIP are sensitive to both these drugs and accumulate higher levels of DNA gaps and breakage following treatment. We can reverse this breakage and sensitivity by preventing the formation of DNA gaps in cells lacking MRNIP.

Our studies also indicate that most normal and cancer cells contain MRNIP. However, we find that a subset of ovarian cancer cells have no detectable MRNIP. This raises the possibility that certain patients suffer from cancers that lack MRNIP, and who may therefore respond well to particular treatments. MRNIP status may therefore prove a useful tool in 'precision medicine', in which information about each individual patient and the cancer from which they suffer is used to determine the most effective treatment.

Our strategy is to advance our knowledge about MRNIP on several levels. We want to understand how MRNIP functions, to...