MUTYH mediates the toxicity of combined DNA 6-thioguanine and UVA radiation

Francesca Grasso, Vitalba Ruggieri, Gabriele De Luca, Paola Leopardi, Maria Teresa Mancuso, Ida Casorelli, Pietro Pichierri, Peter Karran, Margherita Bignami

Research output: Contribution to journalArticle

Abstract

The therapeutic thiopurines, including the immunosuppressant azathioprine (Aza) cause the accumulation of the UVA photosensitizer 6-thioguanine (6-TG) in the DNA of the patients' cells. DNA 6-TG and UVA are synergistically cytotoxic and their interaction causes oxidative damage. The MUTYH DNA glycosylase participates in the base excision repair of oxidized DNA bases. Using Mutyh-null mouse fibroblasts (MEFs) we examined whether MUTYH provides protection against the lethal effects of combined DNA 6-TG/UVA. Surprisingly, Mutyh-null MEFs were more resistant than wild-type MEFs, despite accumulating higher levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG). Their enhanced 6-TG/UVA resistance reflected the absence of the MUTYH protein and MEFs expressing enzymatically-dead human variants were as sensitive as wild-type cells. Consistent with their enhanced resistance, Mutyh-null cells sustained fewer DNA strand breaks and lower levels of chromosomal damage after 6-TG/UVA. Although 6-TG/UVA treatment caused early checkpoint activation irrespective of the MUTYH status, Mutyh-null cells failed to arrest in S-phase at late time points. MUTYH-dependent toxicity was also apparent in vivo. Mutyh-/- mice survived better than wild-type during a 12-month chronic exposure to Aza/UVA treatments that significantly increased levels of skin DNA 8-oxoG. Two squamous cell skin carcinomas arose in Aza/UVA treated Mutyh-/- mice whereas similarly treated wild-type animals remained tumor-free.

Original languageEnglish
Pages (from-to)7481-7492
Number of pages12
JournalOncotarget
Volume6
Issue number10
Publication statusPublished - 2015

    Fingerprint

Keywords

  • 6-thioguanine
  • Azathioprine
  • MUTYH
  • UVA

ASJC Scopus subject areas

  • Oncology

Cite this

Grasso, F., Ruggieri, V., Luca, G. D., Leopardi, P., Mancuso, M. T., Casorelli, I., Pichierri, P., Karran, P., & Bignami, M. (2015). MUTYH mediates the toxicity of combined DNA 6-thioguanine and UVA radiation. Oncotarget, 6(10), 7481-7492.