Understanding the impact of DNA ADP-ribosylation on telomere function in cancer cells

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RESEARCH SUMMARY/ABSTRACT Cancer cells must employ a telomere lengthening mechanism to ensure replicative immortality. 15% of cancer cells utilize Alternative Lengthening of Telomeres (ALT), a homologous recombination-mediated pathway. Perturbation of the ALT mechanism can be achieved by disruption of enzymes involved in ADP-ribosylation, a post-translational modification that regulates several cellular processes including transcription, metabolism, and DNA repair. The pharmacological inhibition of enzymes involved in ADP-ribosylation has proven to be of immense biomedical value in cancer therapy. Over the last 30 years, studies have primarily built on intensive investigation of ADP-ribosylation as a modification that is exclusively found on proteins. Yet, new evidence is emerging that nucleic acids, DNA and RNA, are direct and perhaps even the predominant sources of ADP- ribosylation, especially in the aftermath of DNA damage. This paradigm shift has major implications for our understanding of the physiological function of ADP-ribosylation in ALT. Thus, improving our knowledge of the cellular targets and mechanisms of this new DNA modification will be vital for the development of enhanced ADP-ribose-targeting therapeutics that achieve better clinical outcomes for ALT cancer patients. I found that telomeres, specialized structures at the ends of the chromosomes, are targets of the major ADP-ribosylation enzymes; Poly ADP-ribose Polymerase (PARP1), Poly ADP-ribose Glycohydrolase (PARG), and a newly identified factor known as Terminal ADP-ribose Hydrolase (TARG1). I uncovered that PARP1 coordinates the ADP-ribosylation of telomeric DNA sequences and that TARG1, acting in conjunction with PARG, is responsible for the removal ADP-ribose from telomeric DNA. Furthermore, I show that the disruption of TARG1 expression provokes replicative complications at ALT telomeres that may have catastrophic consequences for cancer cell viability. In Aim 1, I will further assess the impact of DNA ADP-ribosylation and defects in factors that regulate its removal on telomere function and ALT. In Aim 2, I will dissect the impact of co-suppression of TARG1 and PARG, factors that regulate DNA ADP-ribosylation, on cancer cell viability, and the contribution of telomere dysfunction therein. This study will provide new and crucial knowledge on the novel and fundamental role of ADP-ribosylation in ALT. By exploring the impact that its deregulation has on ALT, this study will contribute new insights into how the deregulation of ADP-ribosylation contributes to cancer treatment.