Protein oxidation and DNA repair inhibition by 6-thioguanine and UVA radiation

J Invest Dermatol. 2014 May;134(5):1408-1417. doi: 10.1038/jid.2013.509. Epub 2013 Nov 27.

Abstract

Damage to skin DNA by solar UV is largely unavoidable, and an optimal cellular response to it requires the coordinated operation of proteins in numerous pathways. A fully functional DNA repair proteome for removing harmful DNA lesions is a prerequisite for an appropriate DNA damage response. Genetically determined failure to repair UV-induced DNA damage is associated with skin photosensitivity and increased skin cancer risk. Patients treated with immunosuppressant/anti-inflammatory thiopurines are also photosensitive and have high rates of sun-related skin cancer. Their DNA contains the base analog 6-thioguanine (6-TG), which acts as a UVA photosensitizer to generate reactive oxygen species (ROS), predominantly singlet oxygen ((1)O2). ROS damage both DNA and proteins. Here we show that UVA irradiation of cultured human cells containing DNA 6-TG causes significant protein oxidation and damages components of the DNA repair proteome, including the Ku, OGG-1, MYH, and RPA proteins. Assays of DNA repair in intact cells or in cell extracts indicate that this protein damage compromises DNA break rejoining and base and nucleotide excision repair. As these experimental conditions simulate those in the skin of patients taking thiopurines, our findings suggest a mechanism whereby UVA in sunlight may contribute to skin carcinogenesis in immunosuppressed patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / adverse effects
  • Antimetabolites, Antineoplastic / pharmacology
  • Cricetinae
  • DNA End-Joining Repair / drug effects
  • DNA End-Joining Repair / radiation effects
  • DNA Glycosylases / metabolism
  • DNA Helicases / metabolism
  • DNA Repair / drug effects*
  • DNA Repair / radiation effects*
  • Fibroblasts / cytology
  • HeLa Cells
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Ku Autoantigen
  • Leukemia
  • Oxidation-Reduction
  • Photosensitivity Disorders / metabolism*
  • Photosensitivity Disorders / pathology
  • Proteome / metabolism
  • Risk Factors
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / etiology
  • Thioguanine / pharmacology*
  • Ultraviolet Rays / adverse effects*

Substances

  • Anti-Inflammatory Agents
  • Antimetabolites, Antineoplastic
  • Immunosuppressive Agents
  • Proteome
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human
  • DNA Helicases
  • XRCC5 protein, human
  • Ku Autoantigen
  • Thioguanine