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Poly(ADP-ribose): novel functions for an old molecule

Key Points

  • Poly(ADP-ribose) (PAR) is synthesized from NAD+ by PAR polymerases (PARPs) and regulates many physiological processes such as the maintenance of DNA integrity, gene expression and cell division.

  • PARPs form a superfamily of 17 members in humans, and display diverse subcellular distributions and functions. Some members might function together and possess overlapping properties.

  • PAR that is synthesized in response to DNA-strand breaks is a DNA-damage signalling molecule that allows a rapid and efficient cellular evaluation of the damage range. It is also an essential recruiting molecule that, in a few seconds, concentrates key factors of the single-strand break repair pathway at the site of the lesion.

  • The poly(ADP-ribosyl)ation of histones that are associated with open chromatin conformation at the DNA-damage site provided the first clue to the roles of PAR as an epigenetic modification. Recent evidence revealed an important role of PAR in the epigenetic regulation of chromatin structure and in gene expression under physiological conditions in which the integrity of the DNA is not affected.

  • The dogma that the DNA-damage-dependent PARP-1 is activated by DNA-strand breaks has to be reconsidered now due to recent studies that showed the activation of PARP-1 in the absence of DNA interruptions. Elucidating the triggers is currently one of our most exciting challenges.

  • PARP-1 and PAR play key roles in various acute and chronic inflammatory disorders as well as in a number of degenerative diseases by contributing to the caspase-independent, apoptosis-inducing factor (AIF)-dependent cell death. PARP inhibition confers protection to these pathologies.

  • PARP inhibitors have promising pharmacological applications in potentializing the effect of antitumour drugs in cancer therapy as well as in the treatment of inflammatory, neurological and cardiac disorders.

  • Emerging evidence indicates a possible functional interplay between the PAR metabolic pathway and the SIRT1-mediated deacetylation pathway in the regulation of chromatin structure and function that is associated with broad biological activities.

Abstract

The addition to proteins of the negatively charged polymer of ADP-ribose (PAR), which is synthesized by PAR polymerases (PARPs) from NAD+, is a unique post-translational modification. It regulates not only cell survival and cell-death programmes, but also an increasing number of other biological functions with which novel members of the PARP family have been associated. These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism.

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Figure 1: Metabolism of poly(ADP-ribose) during DNA damage and repair.
Figure 2: Structural alignment of PARP-1, PARP-2 and Corynebacterium diphtheriae toxin.
Figure 3: The PARP superfamily.
Figure 4: PARP-1 in the repair of single-strand breaks.
Figure 5: PARP at the crossroad of survival and inflammation.

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Acknowledgements

The authors acknowledge the Centre National de la Recherche Scientifique, Association pour la Recherche contre le Cancer, Electricité de France, Ligue contre le Cancer, Commissariat à l'Energie Atomique and Agence Nationale pour la Recherche for their support. The authors also thank J. Ménissier-de Murcia for critical comments and suggestions on the manuscript and apologize to our colleagues for the omission of many pertinent references owing to space limitations.

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Glossary

Orthologues

Functionally related genes from different species that have evolved from the same ancestral gene.

Macro domain

A domain that constitutes the non-histone part of histone variant macroH2A. Some macro domains can bind ADP-ribose derivatives.

HMG proteins

A large protein family of small non-histone components of chromatin that function in higher-order chromatin structure.

Heterochromatin

A highly condensed and transcriptionally less active form of chromatin that is found at defined sites, such as centromeres, silencer DNA elements or telomeres.

Centromere

The region in eukaryote chromosomes where daughter chromatids are joined together, and on which the kinetochore assembles.

Centrosome

A structure that forms close to the nucleus in eukaryotic cells during interphase; it comprises a pair of centrioles, satellite bodies and a cytoplasmic zone, and, in animal cells, serves as the main microtubule-organizing centre.

WWE domain

A putative protein–protein interaction motif that contains two conserved Trp residues and one Glu residue.

CCCH zinc finger

A zinc-finger protein motif of the CX7–11CX3–9CX3H type that is a putative RNA-binding module.

Exosome

A complex of several exonucleases that functions in nuclei and the cytoplasm in several different RNA-processing and RNA-degradation pathways.

G1–S restriction point

Cells that progress through this cell-cycle checkpoint are committed to enter S phase.

SSBR/BER

(Single-strand break repair/base-excision repair). Repair pathways that are involved in the processing and repair of single-strand-DNA breaks that can arise indirectly as normal intermediates of DNA-base-excision repair or directly from the cleavage of the sugar–phosphate backbone.

Homologous recombination

A mechanism for the repair of double-strand-DNA breaks that uses a homologous double-stranded DNA molecule as a template for the repair of the broken DNA.

Non-homologous end joining

The predominant repair pathway that is used in mammals to repair double-strand-DNA breaks. No homology is required between the joined DNA strands.

Epigenetic regulation

The regulation of gene expression that occurs through transcriptional or post-transcriptional mechanisms, rather than the 'genetic' alteration of the genomic DNA sequence.

Mediator complex

A multiprotein complex that is recruited to some transcriptional enhancers by activator proteins.

Insulator

A chromatin boundary element that regulates gene activity in complex genetic loci by adopting a specialized chromatin structure and by preventing the interaction between enhancers and promoters.

Imprinted loci

The loci of a gene that is expressed from only one of the two parental copies. Which one is expressed is dependent on the sex of the parent from which the gene was derived.

Pericentric heterochromatin

A region of chromatin that is found adjacent to the centromere and that remains condensed throughout the cell cycle. It is considered to be typically constitutive heterochromatin.

Chromosomal passenger protein

A protein that associates with chromosomes during the early stages of mitosis, then with the spindle midzone and the equatorial cortex during anaphase and telophase, and with the midbody during exit from mitosis.

Spindle checkpoint

The molecular process that specifically controls the assembly of the kinetochore on the chromosomal centromere and the timing of kinetochore dissociation. Dissociation involves the movement of the kinetochores, along with their attached sister chromatids, to opposite poles of the mitotic spindle during anaphase.

Kinetochore

A large multiprotein complex that assembles onto the centromere of the chromosome and that links the chromosome to the microtubules of the mitotic spindle.

Chromatinolysis

The cleavage of DNA into high-molecular-weight (50 kb) fragments during caspase-independent cell death.

Mitochondrial membrane potential

An electrochemical gradient that occurs across the mitochondrial membrane, and is also referred to as ΔΨm. A loss in membrane potential serves as an early indicator of the initiation of cellular apoptosis.

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Schreiber, V., Dantzer, F., Ame, JC. et al. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7, 517–528 (2006). https://doi.org/10.1038/nrm1963

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