Poly(ADP-ribose)

PARadigms and PARadoxes

Alexander Bürkle, L. Virag

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification (PTM) catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARPs use NAD+ as substrate and upon cleaving off nicotinamide they transfer the ADP-ribosyl moiety covalently to suitable acceptor proteins and elongate the chain by adding further ADP-ribose units to create a branched polymer, termed poly(ADP-ribose) (PAR), which is rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3). In recent years several key discoveries changed the way we look at the biological roles and mode of operation of PARylation. These paradigm shifts include but are not limited to (1) a single PARP enzyme expanding to a PARP family; (2) DNA-break dependent activation extended to several other DNA dependent and independent PARP-activation mechanisms; (3) one molecular mechanism (covalent PARylation of target proteins) underlying the biological effect of PARPs is now complemented by several other mechanisms such as protein-protein interactions, PAR signaling, modulation of NAD+ pools and (4) one principal biological role in DNA damage sensing expanded to numerous, diverse biological functions identifying PARP-1 as a real moonlighting protein. Here we review the most important paradigm shifts in PARylation research and also highlight some of the many controversial issues (or paradoxes) of the field such as (1) the mostly synergistic and not antagonistic biological effects of PARP-1 and PARG; (2) mitochondrial PARylation and PAR decomposition, (3) the cross-talk between PARylation and signaling pathways (protein kinases, phosphatases, calcium) and the (4) divergent roles of PARP/PARylation in longevity and in age-related diseases.

Original languageEnglish
Pages (from-to)1046-1065
Number of pages20
JournalMolecular Aspects of Medicine
Volume34
Issue number6
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Adenosine Diphosphate
Proteins
ADP-ribosylarginine hydrolase
NAD
DNA
Chemical activation
Adenosine Diphosphate Ribose
DNA Breaks
Niacinamide
Phosphoprotein Phosphatases
Enzymes
Post Translational Protein Processing
Phosphoric Monoester Hydrolases
Protein Kinases
DNA Damage
Polymers
Modulation
Calcium

Keywords

  • Apoptosis
  • Calcium
  • Cell death
  • Chromatin structure
  • DNA repair
  • Kinase
  • Mitochondria
  • Necrosis
  • Poly(ADP-ribose) glycohydrolase
  • Poly(ADP-ribose) polymerase
  • Signaling
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Clinical Biochemistry
  • Medicine(all)

Cite this

Poly(ADP-ribose) : PARadigms and PARadoxes. / Bürkle, Alexander; Virag, L.

In: Molecular Aspects of Medicine, Vol. 34, No. 6, 12.2013, p. 1046-1065.

Research output: Contribution to journalArticle

Bürkle, Alexander ; Virag, L. / Poly(ADP-ribose) : PARadigms and PARadoxes. In: Molecular Aspects of Medicine. 2013 ; Vol. 34, No. 6. pp. 1046-1065.
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