Daughter Strand DNA Gaps as Determinants of Chemoresistance

All cells (including cancer cells) must copy their DNA before they can multiply, and many chemotherapies target this process. Patients with mutations in the BRCA genes respond well to precision medicines called PARP inhibitors. Recently, we and others have found that cancer cell sensitivity to PARP inhibitors is at least partly due to the formation of excessive gaps in DNA while it is being copied.

We identified a protein called MRNIP, which we find also suppresses DNA gaps in tumour cells by regulating a DNA-digesting enzyme called MRE11, and we show that this gap formation makes MRNIP-deficient cancer cells sensitive to PARP inhibitors. Paradoxically, these cells are highly resistant to Gemcitabine, a first-line therapy for pancreatic cancer. We propose a new model via which hyperactivation of MRE11 can alternatively promote cancer cell survival or death.

We will explore these new findings and test our hypotheses by targeting MRNIP in breast, pancreatic and ovarian cancer cells, examining the prevalence of DNA gaps and cell sensitivity to PARP inhibitors, Gemcitabine, and novel drugs targeting polymerases, which are cellular factors that can fill in DNA gaps. Our work will delineate novel mechanisms dictating chemosensitivity, which may prove clinically and commercially relevant.