[Frontiers in Bioscience 14, 72-111, January 1, 2009]

The molecular "Jekyll and Hyde" duality of PARP1 in cell death and cell survival

Paul O. Hassa

European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Programmed cell death mechanisms
3.1. Apoptosis
3.1.1. Collective apoptotic cell death
3.2. Macroautophagocytotic cell death
3.3. Programmed-necrotic cell death
3.4. Mitotic catastrophe
3.5. Senescence induced cell death?
4. PARP1-mediated cell death
4.1. PARP1-mediated programmed-necrotic cell death
4.1.1. NAD depletion/PARP1-suicide Model
4.1.2. AIF shuttling/signaling model
4.1.2.1. Molecular mechanisms underlying the PARP1-mediated shuttling of AIF
4.1.2.1.1. NAD/ATP depletion
4.1.2.1.2. Enhanced cytosolic retention of AIF by HSP70 in Parp1 knockout mice
4.1.2.1.3. Free poly-ADP-ribose could serve as nucleus-to-mitochondria signaling molecule and death signal
4.1.2.1.4. Shuttling of nuclear proteinaceous pro-necrotic factors to mitochondria
4.1.2.1.5. Activation of an unknown cytoplasmic isoform of PARP1 or PARP2
4.1.3. Kinase-mediated activation of PARP1 in programmed-necrotic cell death
4.1.4. PARP1 independent AIF mediated cell death processes
4.1.5. Secondary necrosis in the surrounding tissue as a result of poly-ADP-ribosylation mediated release of HMGB1?
4.1.6. The Role of other PARP family members and PARGs in necrotic cell death
4.1.6.1. PARP2
4.1.6.2. Tankyrases
4.1.6.3. Poly-ADP-ribose glycohydrolase (PARG)
4.2. PARP1-mediated poly-ADP-ribosylation in apoptosis
4.2.1. Caspase-mediated cleavage of PARP1; a proposed hallmark of apoptosis
4.2.2. Poly-ADP-ribosylation induced changes of chromatin structure during apoptosis
4.2.3. Poly-ADP-ribosylation/PARG-mediated activation of TRPM calcium channels during oxidant induced apoptosis
4.2.4. PARP/PARG-mediated hyperglycation and glyoxidation could induce apoptotic cell death
4.2.5. Proposed role of poly-ADP-ribosylation of p53 in apoptosis
4.2.6. PARP1 mediated transcriptional upregulation of pro-apoptotic genes
4.3. Role of PARP1 in programmed macroautophagocytotic cell death
4.4. PARP1 may regulate senescence-induced programmed cell death
5. PARPs as survival Factors
5.1. PARP1 is essential for cell cycle progression of highly proliferating cells upon cellular stress
5.2. PARP1 and PARP2 are essential for repression of DNA damage induced apoptotic cell death
5.3. PARP1 and PARP2 serve as survival factors for neuronal cells by modulating ROS levels
5.4. ADP-ribose-AMP/cAMP-mediated AMPK / survival signaling
6. Poly-ADP-ribosylation/PARP1-mediated switches between PCD and cell survival
6.1. A PARP1/ poly-ADP-ribosylation-mediated switch between different PCD pathways?
6.2. A poly-ADP-ribose code for cell death and cell survival
6.3. Gender effects
6.4. Crosstalk of ADP-ribosylation and other NAD+-dependent reactions in cell death and survival pathways
8. Conclusions and future perspectives
9. Acknowledgement

1. ABSTRACT

The current literature clearly indicates that PARP1 but also PARP2 play a pivotal role in modulating the cellular responses to stress. Genetic and pharmacological studies demonstrated that overactivation of PARP1 is a key mediator of programmed-necrotic cell death in vivo. PARP1 appears to be also involved in programmed cell death processes others than necrosis, such as apoptosis or macroautophagocytotic cell death. On the other hand, growing evidence suggests that both PARP1 and PARP2 are multi-faced enzymes also playing important roles in cell survival processes. PARP1 and PARP2 were shown to be required for the maintenance of genomic integrity and to act as a survival factor for highly proliferating cells such as stem cells but also non-proliferating neuronal cells against cell death induced by oxidative stress under mild and moderate progressive damage in vivo. This review briefly summarizes the recent findings, which support a crucial role of PARP1 in different programmed cell death and cell survival processes. A special focus is placed on the proposed molecular mechanisms underlying the "Jekyll and Hyde" duality of PARP1 in cell death and cell survival pathways. A potential crosstalk between PARP1, PARP2 and other NAD+-dependent ADP-ribosyling enzymes such as Sirtuins and CD38 in cell death and survival pathways is discussed.