Abstract

Poly(ADP-ribose)-deficient cell lines, developed by us, showed hypersensitivity to all the alkylating and platinating agents, UV, X-ray, and their mimetics. In contrast, they were extremely resistant to various kinds of topoisomeraseIIa inhibitors such as VP-16, adriamycin, and merbarone. We were bewildered by the fact that why poly(ADP-ribose) deficiency would result in hypersensitivity to certain classes of DNA damaging agents while developing resistance to others. We argued that since PARP and NAD+ serve as a stress-responsive system their absence could lead to the induction of another stress protein families. Indeed, we discovered that absence of poly(ADP-ribose) caused many-fold increase in GRP78 level with concomitant, significantly, attenuated level of topoisomeraseIIa. In subsequent experiments, using various approaches to induce GRP78, we showed that induction of GRP78 was associated with a significant decrease in both the level and activity of topoisomerase IIa which was sufficient to explain why poly(ADP-ribose)-deficient cells were resistant to topoisomeraseIIa inhibitors. In another set of experiments, using topoisomeraseIIa-deficient/dysfunctional cell lines and GRP78 overexpressed cell lines, we showed that topoisomeraseIIa was required for the repair of DNA damage inflicted by various alkylating and platinating agents and X-rays. Combining all these observations we propose the following pathway.Deficiency of poly(ADP-ribose) –> Overexpression of GRP78 –> Down-regulation of topoisomerase IIa –> Interference with DNA repair –> Sensitivity or resistance to DNA damaging agents.However, with a cautionary note, we suggest the existence of many more different pathways, which may not be mutually exclusive, that can account for the role of poly(ADP-ribose) in DNA repair. References: 1.Chatterjee S, Berger NA: Poly(ADP-ribose) polymerase in response to DNA damage. In: Nicoloff JA, Hoekstra M (Eds): DNA Damage and Repair: Vol 2, DNA Repair in Higher Eucaryotes. Chapter 22, Humana Press Inc. 1998, 487-515 2.Hirota H, Gosky D, Berger SJ, Berger NA, Chatterjee S: Interference with topoisomerase IIa potentiates melphalan cytotoxicity. Int J Oncology, 2002; 20: 311-318 3.Chatterjee S: Resistance or sensitivity to anti-cancer drugs: An emerging arena involving stress protein GRP78. Recent Research Developments in Cancer (Vol 4), 2002; 161-176 4.Gosky D, Chatterjee S: Down-regulation of topoisomerase IIa is caused by up-regulation of GRP78. Biochem Biophys Res Commun, 2003; 300: 327-332

Keywords: PARP, Poly(ADP-ribose), Topoisomerase IIa, GRP78, resistance or sensitivity to anticancer agents