Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases

Julio C. Morales, Longshan Li, Farjana J. Fattah, Ying Dong, Erik A. Bey, Malina Patel, Jinming Gao, David A. Boothman

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.

Original languageEnglish (US)
Pages (from-to)15-28
Number of pages14
JournalCritical Reviews in Eukaryotic Gene Expression
Volume24
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Poly(ADP-ribose) Polymerases
Neoplasms
DNA Repair
Tankyrases
Apoptosis Inducing Factor
Adenosine Diphosphate Ribose
Recombinational DNA Repair
Mitochondrial Membrane Potential
Telomerase
Homologous Recombination
Telomere
NAD
Chromatin
Proteins
Cell Death
Adenosine Triphosphate
Clinical Trials
DNA
Enzymes
Therapeutics

Keywords

  • β-lap
  • Chromatin
  • DNA damage
  • DNA repair
  • Hyperactivation
  • Metabolism
  • Parp1
  • Programmed necrosis
  • Synthetic lethality

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. / Morales, Julio C.; Li, Longshan; Fattah, Farjana J.; Dong, Ying; Bey, Erik A.; Patel, Malina; Gao, Jinming; Boothman, David A.

In: Critical Reviews in Eukaryotic Gene Expression, Vol. 24, No. 1, 2014, p. 15-28.

Research output: Contribution to journalArticle

Morales, Julio C. ; Li, Longshan ; Fattah, Farjana J. ; Dong, Ying ; Bey, Erik A. ; Patel, Malina ; Gao, Jinming ; Boothman, David A. / Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. In: Critical Reviews in Eukaryotic Gene Expression. 2014 ; Vol. 24, No. 1. pp. 15-28.
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