Cells rely on PARP enzymes to attach long chains of ADP-ribose units onto proteins, a chemical modification that controls DNA repair, chromosome structure, and cell division. When these PARP-regulated pathways go awry, genome stability breaks down, contributing to cancer and cardiovascular disease. Researchers already use PARP inhibitors to treat hereditary breast and ovarian cancers, but the molecular details of how these pathways work—and how to block them more precisely—remain poorly understood. This project focuses on two underexplored angles: the enzyme PARG, which removes ADP-ribose chains, and unknown proteins that mediate PARP signals during DNA repair. The team will combine biochemistry, cell biology, and structural studies to develop the first specific cell-permeable inhibitors of human PARG, and to screen for new DNA repair factors that PARPs regulate. If successful, these inhibitors could offer an alternative to current PARP-targeted cancer therapies, potentially bypassing resistance mechanisms. Characterising novel repair factors may also reveal fresh drug targets. The work is fundamental science—it aims to map the basic machinery of genome maintenance—but it directly feeds into the design of next-generation cancer treatments.
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Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the molecular players involved in these pathways and their mechanism s of regulation remain poorly understood. In recent years, blocking the PARP-regulated pathways using small-molecule inhibitors has become a promising strategy for treatment of cancer and acute cardiovascular conditions. For example, cell-permeable inhibitors targeting the PARP enzymes involved in DNA break repair demonstrated efficacy against certain types of cancer, such as hereditary breast or ovarian cancers. The intriguing alternative approaches to the chemical inhibition of PARPs include t argeting downstream protein effectors of PARP signalling and targeting PARG, the major enzyme that removes poly(ADP-ribosyl)ation. In the proposed studies, we will utilise a combination of biochemistry, cell biology and structural studies to improve our understanding of the function and regulation of PARG enzyme, and also to attempt developing the first specific cell-permeable human PARG inhibitors. Another goal of our studies is to screen for novel PARP-regulated DNA repair factors. Some of the identified proteins will be further characterised to elucidate their exact biochemical functions and regulation in DNA repair. Furthermore, we will explore the potential of these proteins to be exploited as targets for small molecule inhibitor design and cancer therapy.
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