Cargando…

New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways

BACKGROUND: Oxidative damage to DNA, if not repaired, can be both miscoding and blocking. These genetic alterations can lead to mutations and/or cell death, which in turn cause cancer and aging. Oxidized DNA bases are substrates for two overlapping repair pathways: base excision (BER) and nucleotide...

Descripción completa

Detalles Bibliográficos
Autores principales: Redrejo-Rodríguez, Modesto, Saint-Pierre, Christine, Couve, Sophie, Mazouzi, Abdelghani, Ishchenko, Alexander A., Gasparutto, Didier, Saparbaev, Murat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143120/
https://www.ncbi.nlm.nih.gov/pubmed/21799731
http://dx.doi.org/10.1371/journal.pone.0021039
_version_ 1782208885702000640
author Redrejo-Rodríguez, Modesto
Saint-Pierre, Christine
Couve, Sophie
Mazouzi, Abdelghani
Ishchenko, Alexander A.
Gasparutto, Didier
Saparbaev, Murat
author_facet Redrejo-Rodríguez, Modesto
Saint-Pierre, Christine
Couve, Sophie
Mazouzi, Abdelghani
Ishchenko, Alexander A.
Gasparutto, Didier
Saparbaev, Murat
author_sort Redrejo-Rodríguez, Modesto
collection PubMed
description BACKGROUND: Oxidative damage to DNA, if not repaired, can be both miscoding and blocking. These genetic alterations can lead to mutations and/or cell death, which in turn cause cancer and aging. Oxidized DNA bases are substrates for two overlapping repair pathways: base excision (BER) and nucleotide incision repair (NIR). Hydantoin derivatives such as 5-hydroxyhydantoin (5OH-Hyd) and 5-methyl-5-hydroxyhydantoin (5OH-5Me-Hyd), major products of cytosine and thymine oxidative degradation pathways, respectively, have been detected in cancer cells and ancient DNA. Hydantoins are blocking lesions for DNA polymerases and excised by bacterial and yeast DNA glycosylases in the BER pathway. However little is known about repair of pyrimidine-derived hydantoins in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, using both denaturing PAGE and MALDI-TOF MS analyses we report that the bacterial, yeast and human AP endonucleases can incise duplex DNA 5′ next to 5OH-Hyd and 5OH-5Me-Hyd thus initiating the NIR pathway. We have fully reconstituted the NIR pathway for these lesions in vitro using purified human proteins. Depletion of Nfo in E. coli and APE1 in HeLa cells abolishes the NIR activity in cell-free extracts. Importantly, a number of redundant DNA glycosylase activities can excise hydantoin residues, including human NTH1, NEIL1 and NEIL2 and the former protein being a major DNA glycosylase activity in HeLa cells extracts. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that both BER and NIR pathways can compete and/or back-up each other to remove hydantoin DNA lesions in vivo.
format Online
Article
Text
id pubmed-3143120
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-31431202011-07-28 New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways Redrejo-Rodríguez, Modesto Saint-Pierre, Christine Couve, Sophie Mazouzi, Abdelghani Ishchenko, Alexander A. Gasparutto, Didier Saparbaev, Murat PLoS One Research Article BACKGROUND: Oxidative damage to DNA, if not repaired, can be both miscoding and blocking. These genetic alterations can lead to mutations and/or cell death, which in turn cause cancer and aging. Oxidized DNA bases are substrates for two overlapping repair pathways: base excision (BER) and nucleotide incision repair (NIR). Hydantoin derivatives such as 5-hydroxyhydantoin (5OH-Hyd) and 5-methyl-5-hydroxyhydantoin (5OH-5Me-Hyd), major products of cytosine and thymine oxidative degradation pathways, respectively, have been detected in cancer cells and ancient DNA. Hydantoins are blocking lesions for DNA polymerases and excised by bacterial and yeast DNA glycosylases in the BER pathway. However little is known about repair of pyrimidine-derived hydantoins in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, using both denaturing PAGE and MALDI-TOF MS analyses we report that the bacterial, yeast and human AP endonucleases can incise duplex DNA 5′ next to 5OH-Hyd and 5OH-5Me-Hyd thus initiating the NIR pathway. We have fully reconstituted the NIR pathway for these lesions in vitro using purified human proteins. Depletion of Nfo in E. coli and APE1 in HeLa cells abolishes the NIR activity in cell-free extracts. Importantly, a number of redundant DNA glycosylase activities can excise hydantoin residues, including human NTH1, NEIL1 and NEIL2 and the former protein being a major DNA glycosylase activity in HeLa cells extracts. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that both BER and NIR pathways can compete and/or back-up each other to remove hydantoin DNA lesions in vivo. Public Library of Science 2011-07-25 /pmc/articles/PMC3143120/ /pubmed/21799731 http://dx.doi.org/10.1371/journal.pone.0021039 Text en Redrejo-Rodríguez et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Redrejo-Rodríguez, Modesto
Saint-Pierre, Christine
Couve, Sophie
Mazouzi, Abdelghani
Ishchenko, Alexander A.
Gasparutto, Didier
Saparbaev, Murat
New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title_full New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title_fullStr New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title_full_unstemmed New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title_short New Insights in the Removal of the Hydantoins, Oxidation Product of Pyrimidines, via the Base Excision and Nucleotide Incision Repair Pathways
title_sort new insights in the removal of the hydantoins, oxidation product of pyrimidines, via the base excision and nucleotide incision repair pathways
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143120/
https://www.ncbi.nlm.nih.gov/pubmed/21799731
http://dx.doi.org/10.1371/journal.pone.0021039
work_keys_str_mv AT redrejorodriguezmodesto newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT saintpierrechristine newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT couvesophie newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT mazouziabdelghani newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT ishchenkoalexandera newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT gasparuttodidier newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways
AT saparbaevmurat newinsightsintheremovalofthehydantoinsoxidationproductofpyrimidinesviathebaseexcisionandnucleotideincisionrepairpathways