Primary Vestibular Schwannoma Cells Activate p21 and RAD51-Associated DNA Repair following Radiation-Induced DNA Damage

Torin P. Thielhelm, Stefania Goncalves, Scott Welford, Eric A. Mellon, Olena Bracho, Michael Estivill, Clifford Brown, Jacques Morcos, Michael E. Ivan, Fred Telischi, Cristina Fernandez-Valle, Christine T. Dinh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hypothesis:Vestibular Schwannoma (VS) can avoid cell death following radiation injury by entering cell cycle arrest and activating RAD51-related DNA repair.Background:Although the radiobiology of various cancers is well-studied, the radiobiological effects in VS are poorly understood. In this study, we describe how VS cells enter cell cycle arrest (through p21 expression), activate DNA repair (through RAD51 upregulation), and avoid cell death after radiation-induced double-stranded breaks (DSB) in DNA (as measured by γ-H2AX).Methods:Primary human VS cells were cultured on 96-well plates and 16-well culture slides at 10,000cells/well and exposed to either 0 or 18 Gray of radiation. Viability assays were performed at 96h in vitro. Immunofluorescence for γ-H2AX, RAD51, and p21 was performed at 6h.Results:Radiation (18Gy) induced the expression of γ-H2AX, p21, and RAD51 in six cultured VS, suggesting that irradiated VS acquire DSBs, enter cell cycle arrest, and initiate RAD51 DNA repair to evade cell death. However, viability studies demonstrate variable responses in individual VS cells with 3 of 6 VS showing radiation resistance to 18Gy. On further analyses, radiation-resistant VS cells expressed significantly more p21 than radiation-responsive tumors.Conclusions:In response to radiation-induced DNA damage, primary VS cells can enter cell cycle arrest and express RAD51 DNA repair mechanisms to avoid cell death. Radioresistant VS cells may mount a more robust p21 response to ensure sufficient time for DNA repair. Further investigation into DNA repair proteins and cell cycle checkpoints may provide important insight on the radiobiology of VS and mechanisms for resistance.

Original languageEnglish (US)
Pages (from-to)E1600-E1608
JournalOtology and Neurotology
Volume42
Issue number10
DOIs
StatePublished - Dec 1 2021

Keywords

  • Cell cycle arrest
  • H2AX
  • p21
  • RAD51
  • Radiation
  • Resistance
  • Vestibular schwannoma
  • VS

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Sensory Systems
  • Clinical Neurology

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