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AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe

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 per...

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Autores principales: Nilsen, Line, Forstrøm, Rune J., Bjørås, Magnar, Alseth, Ingrun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3300018/
https://www.ncbi.nlm.nih.gov/pubmed/22084197
http://dx.doi.org/10.1093/nar/gkr933
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author Nilsen, Line
Forstrøm, Rune J.
Bjørås, Magnar
Alseth, Ingrun
author_facet Nilsen, Line
Forstrøm, Rune J.
Bjørås, Magnar
Alseth, Ingrun
author_sort Nilsen, Line
collection PubMed
description 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.
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spelling pubmed-33000182012-03-13 AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe Nilsen, Line Forstrøm, Rune J. Bjørås, Magnar Alseth, Ingrun Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2012-03 2011-11-14 /pmc/articles/PMC3300018/ /pubmed/22084197 http://dx.doi.org/10.1093/nar/gkr933 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Nilsen, Line
Forstrøm, Rune J.
Bjørås, Magnar
Alseth, Ingrun
AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title_full AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title_fullStr AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title_full_unstemmed AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title_short AP endonuclease independent repair of abasic sites in Schizosaccharomyces pombe
title_sort ap endonuclease independent repair of abasic sites in schizosaccharomyces pombe
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3300018/
https://www.ncbi.nlm.nih.gov/pubmed/22084197
http://dx.doi.org/10.1093/nar/gkr933
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