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首页> 外文期刊>Molecular and Cellular Biology >trans-dominant inhibition of poly(ADP-ribosyl)ation sensitizes cells against γ-irradiation and N-methyl-N'-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon
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trans-dominant inhibition of poly(ADP-ribosyl)ation sensitizes cells against γ-irradiation and N-methyl-N'-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon

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摘要

Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear proteins catalyzed by poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30), with NAD+ serving as the substrate. PARP is strongly activated upon recognition of DNA strand breaks by its DNA-binding domain. Experiments with low-molecular-weight inhibitors of PARP have led to the view that PARP activity plays a role in DNA repair and possibly also in DNA replication, cell proliferation, and differentiation. Accumulating evidence for nonspecific inhibitor effects prompted us to develop a molecular genetic system to inhibit PARP in living cells, i.e., to overexpress selectively the DNA-binding domain of PARP as a dominant negative mutant. Here we report on a cell culture system which allows inducible, high-level expression of the DNA-binding domain. Induction of this domain leads to about 90 reduction of poly(ADP-ribose) accumulation after γ-irradiation and sensitizes cells to the cytotoxic effect of γ-irradiation and of N-methyl-N'-nitro-N- nitrosoguanidine. In contrast, induction does not affect normal cellular proliferation or the replication of a transfected polyomavirus replicon. Thus, trans-dominant inhibition of the poly(ADP-ribose) accumulation occurring after γ-irradiation or N-methyl-N'-nitro-N- nitrosoguanidine is specifically associated with a disturbance of the cellular recovery from the inflicted damage.

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