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

Tanima Sengupta, Maria Lyngaas Torgersen, Henok Kassahun, T. Vellai, Anne Simonsen, Hilde Nilsen

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Article number2578
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 2013

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
DNA Mismatch Repair
Autophagy
DNA Repair
Repair
deoxyribonucleic acid
DNA Damage
Caenorhabditis elegans
DNA
damage
Fluorouracil
activation
Single-Stranded DNA Breaks
Chemical activation
induction
Molecular Biology
Processing
Cell Death
death
toxicity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. / Sengupta, Tanima; Torgersen, Maria Lyngaas; Kassahun, Henok; Vellai, T.; Simonsen, Anne; Nilsen, Hilde.

In: Nature Communications, Vol. 4, 2578, 2013.

Research output: Contribution to journalArticle

Sengupta, Tanima ; Torgersen, Maria Lyngaas ; Kassahun, Henok ; Vellai, T. ; Simonsen, Anne ; Nilsen, Hilde. / Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. In: Nature Communications. 2013 ; Vol. 4.
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