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New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs

Key Points

  • Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification in which ADP-ribose units are added to Glu, Asp and Lys residues of target (or acceptor) proteins by members of the poly(ADP-ribose) polymerase (PARP) family. Seventeen PARP family members have been identified on the basis of homology to PARP1, which is the founding member of the PARP family.

  • PARylation is important for cellular signalling pathways, cytoplasmic and nuclear functions and the response to cellular stress.

  • A number of proteins with poly(ADP-ribose) (PAR) degrading activities have been characterized, such as the endo- and exoglycohydrolase poly(ADP-ribose) glycohydrolase (PARG). PARG promotes the rapid catabolic destruction of PAR almost immediately after synthesis, thus allowing temporal control of PAR functions.

  • Recognition of and binding to PAR occurs through four distinct protein modules: PAR-binding motifs (PBMs), PAR-binding zinc-finger (PBZ) domains, macrodomain folds and WWE domains. Some of these domains are found in PARPs themselves.

  • New evidence has shown that the activation and destruction of PAR modifications can alter protein substrate specificity, localization and stability, and these findings implicate PARPs as a promising target for therapeutic intervention in human disease.

  • The key mechanisms by which PARylation regulates many cellular responses include the inhibition of protein–protein or protein–DNA interactions, nucleation of protein localization and interaction scaffolds, as well as the regulation of other protein modifications, such as ubiquitylation.

  • The involvement of PARP proteins in DNA damage detection and repair, telomere maintenance, and stress responses and recovery gives hope for the use of PARP inhibition as a means for selective 'next generation' therapies for cancer, as well as stress-related diseases that exhibit pro-inflammatory signatures (for example, cardiovascular diseases, stroke, metabolic disorders, diabetes, and autoimmunity). As such, PARPs have recently been targeted with small molecules in clinical trials for a number of human diseases.

Abstract

Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses. PARPs act in a complex response network that is driven by the cellular, molecular and chemical biology of poly(ADP-ribose) (PAR). This PAR-dependent response network is crucial for a broad array of physiological and pathological responses and thus is a good target for chemical therapeutics for several diseases.

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Figure 1: Structure of PAR and mechanisms of PAR catalysis and glycohydrolysis.
Figure 2: PARP1 activation and target selection.
Figure 3: PAR-dependent ubiquitylation and the human disease cherubism.
Figure 4: Cellular functions of PAR and the PAR-dependent recruitment of factors to sites of DNA damage.
Figure 5: Recognition strategies and functions of PAR-binding modules.

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Glossary

SUMOylation

The process of covalently attaching the small ubiquitin-like modifier (SUMO), which is a small protein, to specific Lys residues on target proteins through an isopeptide bond.

Non-homologous end-joining

(NHEJ). A DNA repair pathway that repairs double-strand breaks in DNA. In this pathway the break ends are directly ligated without the need for a homologous template.

Homologous recombination

A type of genetic recombination in which nucleotide sequences are exchanged between two homologous DNA molecules. It is used by cells during S phase of the cell cycle to eliminate deleterious lesions, such as double-strand breaks, from chromosomes.

Cajal bodies

Spherical suborganellar structures that are located in the nuclei of proliferative cells. They are thought to mediate RNA-related metabolic processes, including small nuclear ribonucleoprotein particle (snRNP) biogenesis, maturation and recycling, as well as histone mRNA processing and telomere maintenance.

Mitotic catastrophe

Cell death that is linked to delayed mitosis and that occurs as a result of aberrant chromosome segregation, chromosome fusions or other types of DNA damage.

Base excision repair

A DNA repair mechanism that primarily removes small, nonhelix-distorting base lesions from the genome, which might otherwise cause mutations during DNA replication.

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Gibson, B., Kraus, W. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13, 411–424 (2012). https://doi.org/10.1038/nrm3376

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