[Frontiers in Bioscience 13, 3046-3082, January 1, 2008]

The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases

Paul O. Hassa1, Michael O. Hottiger2

1European Molecular Biology Laboratory (EMBL), Gene Expression Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany, 2Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich Winterthurerstrasse 190, 8057 Zurich, Switzerland

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Poly-ADP-ribosylation reaction cycle
3.1. Structures of free and protein associated poly-ADP-ribose
3.2. Functional consequences of poly-ADP-ribose-protein interactions
3.3. Poly-ADP-ribose-binding modules
4. Structures and classification of the bona fide PARP family members
4.1. Regulation of PARP enzymatic activities
5. Functional characterization of the PARP family members
5.1. Subgroup I
5.1.1. PARP1
5.1.1.1. Functions
5.1.1.1.1. Architectural corepressor/coactivator activity
5.1.1.1.2. Modulation of the chromatin structure
5.1.1.1.3. PARP1/poly-ADP-ribosylation-mediated cell death
5.1.2. PARP2
5.1.3. PARP3
5.2. Subgroup II
6.2.1. PARP4/vPARP
5.3. Subgroup III
5.3.1. PARP5/tankyrase-1
5.3.2. PARP6/tankyrase-2
6. Structures, classification and functions of the PARGs
7. Cross-talk among PARPs, mARTs and other ADP-ribosylating enzymes
7.1. Regulation through NAD levels
7.2. Regulation through trans-ADP-ribosylation
7.3. Cross-talk of PARPs and mARTs through ADP-ribose metabolites:
8. Pharmacological inhibitors
9. Summary and future perspectives
7. Acknowledgement
11. References

1. ABSTRACT

Poly-ADP-ribose metabolism plays a mayor role in a wide range of biological processes, such as maintenance of genomic stability, transcriptional regulation, energy metabolism and cell death. Poly-ADP-ribose polymerases (PARPs) are an ancient family of enzymes, as evidenced by the poly-ADP-ribosylating activities reported in dinoflagellates and archaebacteria and by the identification of Parp-like genes in eubacterial and archaeabacterial genomes. Six genes encoding "bona fide" PARP enzymes have been identified in mammalians: PARP1, PARP2, PARP3, PARP4/vPARP, PARP5/Tankyrases-1 and PARP6/Tankyrases-2. The best studied of these enzymes PARP1 plays a primary role in the process of poly-ADP-ribosylation. PARP1-mediated poly-ADP-ribosylation has been implicated in the pathogenesis of cancer, inflammatory and neurodegenerative disorders. This review will summarize the novel findings and concepts for PARP enzymes and their poly-ADP-ribosylation activity in the regulation of physiological and pathophysiological processes. A special focus is placed on the proposed molecular mechanisms involved in these processes, such as signaling, regulation of telomere dynamics, remodeling of chromatin structure and transcriptional regulation. A potential functional cross talk between PARP family members and other NAD+-consuming enzymes is discussed.