title: Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy.
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.
authors.affiliation: The Biotechnology Centre, University of Oslo, PO Box 1125 Blindern, N-0317 Oslo, Norway.
authors.forename: Tanima
authors.initials: T
authors.lastname: SenGupta
authors.forename: Maria Lyngaas
authors.initials: ML
authors.lastname: Torgersen
authors.forename: Henok
authors.initials: H
authors.lastname: Kassahun
authors.forename: Tibor
authors.initials: T
authors.lastname: Vellai
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D053843:DNA Mismatch Repair; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D015398:Signal Transduction
chemical_list: D000964:Antimetabolites, Antineoplastic; D029742:Caenorhabditis elegans Proteins; D004706:Endodeoxyribonucleases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C504039:EXO-3 protein, C elegans; C102951:apn-1 protein, C elegans; D005472:Fluorouracil