PARP1 inhibition augments UVB-mediated mitochondrial changes—implications for UV-induced DNA repair and photocarcinogenesis

Csaba Hegedűs, Gábor Boros, Eszter Fidrus, Gréta Nikoletta Kis, Miklós Antal, Tamás Juhász, Eszter Anna Janka, Laura Jankó, György Paragh, Gabriella Emri, Péter Bai, Éva Remenyik

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2 Citations (Scopus)

Abstract

Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM.

Original languageEnglish
Article number5
JournalCancers
Volume12
Issue number1
DOIs
Publication statusPublished - Jan 2020

Keywords

  • Autophagy
  • Biogenesis
  • Carcinogenesis
  • DNA repair
  • DNA repair UVB
  • Metabolism
  • Mitochondria
  • PARP

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hegedűs, C., Boros, G., Fidrus, E., Kis, G. N., Antal, M., Juhász, T., Janka, E. A., Jankó, L., Paragh, G., Emri, G., Bai, P., & Remenyik, É. (2020). PARP1 inhibition augments UVB-mediated mitochondrial changes—implications for UV-induced DNA repair and photocarcinogenesis. Cancers, 12(1), [5]. https://doi.org/10.3390/cancers12010005