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PARP5B is required for nonhomologous end joining during tumorigenesis in vivo

Jianchun Wu1, David L Crowe1

  • 1Department of Diagnostic Sciences, University of Illinois Cancer Center, Chicago, Illinois, USA.

Molecular Carcinogenesis
|October 28, 2021
PubMed

Insights

Loss of PARP5B expression inhibits head and neck squamous cell carcinoma (SCC) growth and metastasis by activating DNA repair pathways. PARP5B inhibition represents a novel targeted cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerases (PARP) are DNA damage sensors crucial for repair factor recruitment.
  • PARP inhibitors are effective in cancers with homologous recombination defects.
  • The role of PARP5B genetic alterations in cancer phenotype remains largely unknown.

Purpose of the Study:

  • To investigate the functional impact of PARP5B loss on head and neck squamous cell carcinoma (SCC) development and phenotype.
  • To explore the potential of PARP5B as a therapeutic target in SCC.

Main Methods:

  • Characterization of a PARP5B null mutation in a carcinogen-induced SCC mouse model.
  • Analysis of tumor growth, differentiation, apoptosis, proliferation, and metastasis.
  • Assessment of DNA damage response pathways, including ATR, ATM, and 53BP1 foci.
  • Investigation of PARP5B null SCC's protein complex composition.
  • Evaluation of etoposide and PARP5B inhibitor XAV939 combination therapy in human SCC cell lines.

Main Results:

  • Reduced PARP5B expression inhibited tumor growth, promoted differentiation and apoptosis, and decreased proliferation and metastasis.
  • PARP5B loss activated ataxia telangiectasia and Rad3 related (ATR) signaling and depleted cancer stem cells.
  • PARP5B null SCC cells showed impaired ATM activation and p53 induction but maintained homologous recombination repair.
  • Combination therapy with etoposide and XAV939 induced senescence and apoptosis in human SCC cells.

Conclusions:

  • PARP5B plays a critical role in head and neck squamous cell carcinoma progression.
  • PARP5B inhibition, particularly in combination with DNA damaging agents, shows promise as a targeted cancer therapy.
Keywords:
DNA damage signalingapoptosiscancer stem cellhomologous recombinationmetastasis

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