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The role of poly(ADP-ribosyl)ation in the adaptive response
1University of Zürich-Tierspital, Institute of Pharmacology and Toxicology, Switzerland.
Abstract:
An involvement of the poly(ADP-ribosyl)ation system in the expression of the adaptive response has been demonstrated with inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase. This enzyme is a key component of a reaction cycle in chromatin, involving dynamic synthesis and degradation of variably sized ADP-ribose polymers in response to DNA strand breaks. The present report reviews recent work focussing on the response of the poly(ADP-ribosyl)ation system in low dose adaptation. The results suggest that adaptation of human cells to minute concentrations of an alkylating agent involves a different activation mechanism for poly(ADP-ribose) polymerase than DNA break-mediated stimulation after high dose treatment. Moreover, adaptation induces the formation of branched polymers with a very high binding affinity for histone tails and selected other proteins. High dose challenge treatment of adapted cells further enhances formation of branched polymers. We propose that apart from sensing DNA nicks, poly(ADP-ribose) polymerase may be part of pathway protecting cells from downstream events of DNA damage.
Insights
The poly(ADP-ribose) polymerase system adapts human cells to low-dose alkylating agents via a unique mechanism, forming branched polymers that may protect against DNA damage.
Area of Science:
- Molecular Biology
- Cellular Response to DNA Damage
Background:
- The poly(ADP-ribosyl)ation system, involving poly(ADP-ribose) polymerase (PARP), plays a role in cellular adaptive responses.
- PARP is a nuclear enzyme central to DNA strand break repair through ADP-ribose polymer synthesis and degradation.
Purpose of the Study:
- To review recent findings on the poly(ADP-ribosyl)ation system's response during low-dose adaptation.
- To investigate the activation mechanisms and polymer characteristics of PARP in adapted cells.
Main Methods:
- Inhibition of poly(ADP-ribose) polymerase to study adaptive responses.
- Analysis of PARP activation and polymer formation in human cells exposed to alkylating agents at varying doses.
Main Results:
- Low-dose adaptation of human cells to alkylating agents utilizes a distinct PARP activation pathway compared to high-dose treatments.
- Adaptation leads to the formation of branched ADP-ribose polymers with high affinity for histones and other proteins.
- Subsequent high-dose challenge in adapted cells amplifies branched polymer formation.
Conclusions:
- Poly(ADP-ribose) polymerase activation in low-dose adaptation differs from DNA break-induced stimulation.
- Branched polymer formation is a key feature of cellular adaptation and may contribute to DNA damage protection.
- PARP might function in pathways that shield cells from the consequences of DNA damage, beyond just sensing nicks.