The elephant and the blind men

Making sense of PARP inhibitors in homologous recombination deficient tumor cells

Silvana B. De Lorenzo, Anand G. Patel, Rachel M. Hurley, Scott H Kaufmann

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is an important component of the base excision repair (BER) pathway as well as a regulator of homologous recombination (HR) and non-homologous end-joining (NHEJ). Previous studies have demonstrated that treatment of HR-deficient cells with PARP inhibitors results in stalled and collapsed replication forks. Consequently, HR-deficient cells are extremely sensitive to PARP inhibitors. Several explanations have been advanced to explain this so-called synthetic lethality between HR deficiency and PARP inhibition: (i) reduction of BER activity leading to enhanced DNA double-strand breaks, which accumulate in the absence of HR; (ii) trapping of inhibited PARP1 at sites of DNA damage, which prevents access of other repair proteins; (iii) failure to initiate HR by poly(ADP-ribose) polymer-dependent BRCA1 recruitment; and (iv) activation of the NHEJ pathway, which selectively induces error-prone repair in HR-deficient cells. Here we review evidence regarding these various explanations for the ability of PARP inhibitors to selectively kill HR-deficient cancer cells and discuss their potential implications.

Original languageEnglish (US)
Article numberArticle 228
JournalFrontiers in Oncology
Volume3 SEP
DOIs
StatePublished - 2013

Fingerprint

Homologous Recombination
Neoplasms
DNA Repair
Poly Adenosine Diphosphate Ribose
Recombinational DNA Repair
Double-Stranded DNA Breaks
Poly(ADP-ribose) Polymerase Inhibitors
DNA Damage
Polymers
Proteins

Keywords

  • BRCA1
  • BRCA2
  • Breast cancer
  • Homologous recombination
  • Non-homologous end joining
  • Ovarian cancer
  • PARP inhibitor
  • Synthetic lethality

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The elephant and the blind men : Making sense of PARP inhibitors in homologous recombination deficient tumor cells. / De Lorenzo, Silvana B.; Patel, Anand G.; Hurley, Rachel M.; Kaufmann, Scott H.

In: Frontiers in Oncology, Vol. 3 SEP, Article 228, 2013.

Research output: Contribution to journalArticle

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