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Cellular responses to DNA damage in the absence of Poly(ADP-ribose) polymerase
Y Le Rhun1, J B Kirkland, G M Shah
1Laboratory for Skin Research, Hospital Research Center for University Laval, CHUL Research Center of CHUQ, Québec, Québec, G1V 4G2, Canada.
Abstract:
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is catalytically activated by DNA strand interruptions. The involvement of PARP has been implicated in different cellular responses to genotoxic damage, including cell survival, DNA repair, transformation, and cell death. However, the exact contribution of PARP polypeptide or its enzymatic product has remained ill defined. Recent studies with two different PARP knock out mice have demonstrated the beneficial role of PARP in maintaining genomic integrity and in survival responses after exposure to whole body gamma-irradiation. Other studies have demonstrated the instrumental role of PARP in death of the neuronal cells after ischemia-reperfusion injury. The recombination inhibiting function of PARP at DNA strand breaks was more evident in a model system deficient in activities of two major DNA strand break binding proteins, PARP and DNA-dependent protein kinase. The present review summarizes similarities and differences obtained with the two PARP knock out mice and reanalyzes the role of PARP in various cellular responses to DNA damage.
Insights
Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA repair and cell survival after DNA damage. Studies with PARP knockout mice reveal its importance in maintaining genomic integrity and neuronal cell death pathways.
Area of Science:
- Molecular Biology
- Genetics
- Cellular Biology
Background:
- Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks.
- PARP is involved in cellular responses to genotoxic damage, including DNA repair, cell survival, and cell death.
- The precise function of PARP and its enzymatic product in these processes remains incompletely understood.
Purpose of the Study:
- To review and compare findings from two different PARP knockout mouse models.
- To re-evaluate the role of PARP in cellular responses to DNA damage.
- To clarify the contribution of PARP to genomic integrity and cell death.
Main Methods:
- Comparative analysis of data from two distinct PARP knockout mouse models.
- Re-analysis of existing studies on PARP's role in DNA damage response.
- Examination of PARP's function in specific cellular contexts like gamma-irradiation and ischemia-reperfusion injury.
Main Results:
- PARP knockout mice demonstrate a beneficial role in maintaining genomic integrity and survival after gamma-irradiation.
- PARP plays a critical role in neuronal cell death following ischemia-reperfusion injury.
- PARP's role in inhibiting recombination at DNA strand breaks is highlighted in models deficient in other DNA repair proteins.
Conclusions:
- PARP is crucial for both DNA repair and cell survival pathways following genotoxic stress.
- PARP has distinct, context-dependent roles in different cell types and injury models.
- Further research is needed to fully elucidate the complex functions of PARP in cellular homeostasis and disease.