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Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy

Author

Listed:
  • Tanima SenGupta

    (The Biotechnology Centre, University of Oslo)

  • Maria Lyngaas Torgersen

    (Institute of Basic Medical Sciences, University of Oslo)

  • Henok Kassahun

    (The Biotechnology Centre, University of Oslo)

  • Tibor Vellai

    (Eötvös Loránd University)

  • Anne Simonsen

    (Institute of Basic Medical Sciences, University of Oslo)

  • Hilde Nilsen

    (The Biotechnology Centre, University of Oslo
    Present address: Institute of Clinical Medicine, University of Oslo, Oslo, Norway, and Akershus University Hospital, N-1478 Lørenskog, Norway)

Abstract

Cellular responses to DNA damage involve distinct DNA repair pathways, such as mismatch repair (MMR) and base excision repair (BER). Using Caenorhabditis elegans as a model system, we present genetic and molecular evidence of a mechanistic link between processing of DNA damage and activation of autophagy. Here we show that the BER AP endonucleases APN-1 and EXO-3 function in the same pathway as MMR, to elicit DNA-directed toxicity in response to 5-fluorouracil, a mainstay of systemic adjuvant treatment of solid cancers. Immunohistochemical analyses suggest that EXO-3 generates the DNA nicks required for MMR activation. Processing of DNA damage via this pathway, in which both BER and MMR enzymes are required, leads to induction of autophagy in C. elegans and human cells. Hence, our data show that MMR- and AP endonuclease-dependent processing of 5-fluorouracil-induced DNA damage leads to checkpoint activation and induction of autophagy, whose hyperactivation contributes to cell death.

Suggested Citation

  • Tanima SenGupta & Maria Lyngaas Torgersen & Henok Kassahun & Tibor Vellai & Anne Simonsen & Hilde Nilsen, 2013. "Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3674
    DOI: 10.1038/ncomms3674
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