Reference - Detail
| RRC ID | 46187 |
|---|---|
| Author | SenGupta T, Torgersen ML, Kassahun H, Vellai T, Simonsen A, Nilsen H. |
| Title | Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. |
| Journal | Nat Commun |
| 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. |
| Volume | 4 |
| Pages | 2674 |
| Published | 2013-1-1 |
| DOI | 10.1038/ncomms3674 |
| PII | ncomms3674 |
| PMID | 24154628 |
| PMC | PMC3826653 |
| MeSH | Animals Antimetabolites, Antineoplastic / pharmacology Autophagy / drug effects Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Cell Cycle Checkpoints / drug effects* Cell Cycle Checkpoints / genetics Cell Line, Tumor DNA Breaks, Single-Stranded / drug effects DNA Mismatch Repair* DNA Repair* DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics* DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism Endodeoxyribonucleases / genetics* Endodeoxyribonucleases / metabolism Fluorouracil / pharmacology Gene Expression Regulation Humans Signal Transduction |
| IF | 12.121 |
| Times Cited | 39 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Resource | |
| C.elegans | tm4374 tm1842 tm853 |