Defining the role of ADP-ribosyltransferases in DNA repair and genome stability

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Preserving the integrity of genetic material through repair of damaged DNA is critical for the health of an organism. My laboratory is focussed on understanding these processes, with specific reference to how a set of enzymes called ADP-ribosyltransferases (ARTs) regulate a variety of DNA repair processes.The best defined role of ARTs is in promoting repair of breaks in the DNA double strand helix. Inhibition of this pathway using small molecule ART inhibitors (ARTi) is being exploited in the clinic to specifically kill tumours with defects in a DNA repair process known as homologous recombination. However, there are several different types of ART in a cell and an emerging theme is that these enzymes can regulate different DNA repair processes. The proposed work will build on our recent exciting new findings addressing how different ARTs function together to repair DNA damage and how inhibiting one ART over others more effectively kills cells following exposure to agents that induce DNA damage. Given currently available ARTi target multiple ARTs, these studies will provide information that underpins the development of more specific ARTi with increased efficacy in the clinic. We will also define novel factors that when inhibited along with ARTs either exaggerate or rescue the sensitivity of cells to DNA damage, identifying pathways that make ART inhibited cells more sensitive or tolerant to radio- or chemotherapy. This work will lead to efforts in improving the efficacy of these agents in the clinic and identify new targets whose inhibition will overcome drug resistance.