title: AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe.
abstract: Abasic (AP) sites are formed spontaneously and are inevitably intermediates during base excision repair of DNA base damages. AP sites are both mutagenic and cytotoxic and key enzymes for their removal are AP endonucleases. However, AP endonuclease independent repair initiated by DNA glycosylases performing β,δ-elimination cleavage of the AP sites has been described in mammalian cells. Here, we describe another AP endonuclease independent repair pathway for removal of AP sites in Schizosaccharomyces pombe that is initiated by a bifunctional DNA glycosylase, Nth1 and followed by cleavage of the baseless sugar residue by tyrosyl phosphodiesterase Tdp1. We propose that repair is completed by the action of a polynucleotide kinase, a DNA polymerase and finally a DNA ligase to seal the gap. A fission yeast double mutant of the major AP endonuclease Apn2 and Tdp1 shows synergistic increase in MMS sensitivity, substantiating that Apn2 and Tdp1 process the same substrate. These results add new knowledge to the complex cellular response to AP sites, which could be exploited in chemotherapy where synthetic lethality is a key strategy of treatment.
authors.affiliation: Department of Microbiology, Oslo University Hospital HF Rikshospitalet, PO Box 4950 Nydalen, N-0424 Oslo, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Nilsen
authors.forename: Rune J
authors.initials: RJ
authors.lastname: Forstrøm
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.forename: Ingrun
authors.initials: I
authors.lastname: Alseth
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D009097:Multienzyme Complexes; C492078:Nth1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C539712:Tdp1 protein, S pombe; D010727:Phosphoric Diester Hydrolases; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes
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