Inhibition of poly (ADP-Ribose) polymerase-1 in telomerase deficient mouse embryonic fibroblasts increases arsenite-induced genome instability

Inhibition of PARP in telomerase deficient MEFs induced an increase in arsenite-induced DNA damage as compared to control cells. Combined inhibition also resulted in enhanced genomic instability, demonstrated by elevated micronuclei induction and chromosomal aberrations with decreased cell survival. In addition, telomerase inhibition in PARP-1 deficient MEFs led to greater telomere shortening and increased genomic instability.Our study demonstrated that the co-inhibition of PARP-1 and telomerase in MEFs rendered cells more susceptible to DNA damaging agents. Hence, these results offer support for the use of combined inhibition of PARP-1 and telomerase as a strategy to minimise the problems associated with long-term telomerase inhibition in cancer therapeutics.Telomeres are specialised dynamic structures at the ends of linear eukaryotic chromosomes consisting of non-coding DNA repeats (TTAGGG)n and associated proteins [1,2]. These terminal DNA-protein complexes function as protective caps preventing chromosomal end-to-end fusions and the recognition of chromosomal ends as damaged DNA [3]. Telomeres shorten with each cell division, eventually triggering senescence [4,5]. In contrast, majority of tumour cells overcome telomere-mediated senescence via the activation of telomerase enzyme [6].Telomerase contains two core components, an RNA subunit (hTERC and mTERC in human and mouse respectively), which provides the template for replenishment of telomeres [7] and a catalytic protein subunit, telomerase reverse transcriptase (hTERT or mTERT) that adds telomeric repeats to existing telomeres [8]. Deletion of mTERC in mice resulted in the shortening of telomeres leading to increased genomic instability and reduction in growth rate [9-11]. In addition, these studies have also demonstrated that no phenotypic differences occur in the first generation mice lacking mTERC component. The abrogation of telomerase results in the reduction in cell proliferation only after telomeres ar