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An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation
Active DNA demethylation (ADDM) in mammals occurs via hydroxylation of 5-methylcytosine (5mC) by TET and/or deamination by AID/APOBEC family enzymes. The resulting 5mC derivatives are removed through the base excision repair (BER) pathway. At present, it is unclear how the cell manages to eliminate...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856981/ https://www.ncbi.nlm.nih.gov/pubmed/26843430 http://dx.doi.org/10.1093/nar/gkw059 |
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author | Grin, Inga Ishchenko, Alexander A. |
author_facet | Grin, Inga Ishchenko, Alexander A. |
author_sort | Grin, Inga |
collection | PubMed |
description | Active DNA demethylation (ADDM) in mammals occurs via hydroxylation of 5-methylcytosine (5mC) by TET and/or deamination by AID/APOBEC family enzymes. The resulting 5mC derivatives are removed through the base excision repair (BER) pathway. At present, it is unclear how the cell manages to eliminate closely spaced 5mC residues whilst avoiding generation of toxic BER intermediates and whether alternative DNA repair pathways participate in ADDM. It has been shown that non-canonical DNA mismatch repair (ncMMR) can remove both alkylated and oxidized nucleotides from DNA. Here, a phagemid DNA containing oxidative base lesions and methylated sites are used to examine the involvement of various DNA repair pathways in ADDM in murine and human cell-free extracts. We demonstrate that, in addition to short-patch BER, 5-hydroxymethyluracil and uracil mispaired with guanine can be processed by ncMMR and long-patch BER with concomitant removal of distant 5mC residues. Furthermore, the presence of multiple mispairs in the same MMR nick/mismatch recognition region together with BER-mediated nick formation promotes proficient ncMMR resulting in the reactivation of an epigenetically silenced reporter gene in murine cells. These findings suggest cooperation between BER and ncMMR in the removal of multiple mismatches that might occur in mammalian cells during ADDM. |
format | Online Article Text |
id | pubmed-4856981 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-48569812016-05-09 An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation Grin, Inga Ishchenko, Alexander A. Nucleic Acids Res Genome Integrity, Repair and Replication Active DNA demethylation (ADDM) in mammals occurs via hydroxylation of 5-methylcytosine (5mC) by TET and/or deamination by AID/APOBEC family enzymes. The resulting 5mC derivatives are removed through the base excision repair (BER) pathway. At present, it is unclear how the cell manages to eliminate closely spaced 5mC residues whilst avoiding generation of toxic BER intermediates and whether alternative DNA repair pathways participate in ADDM. It has been shown that non-canonical DNA mismatch repair (ncMMR) can remove both alkylated and oxidized nucleotides from DNA. Here, a phagemid DNA containing oxidative base lesions and methylated sites are used to examine the involvement of various DNA repair pathways in ADDM in murine and human cell-free extracts. We demonstrate that, in addition to short-patch BER, 5-hydroxymethyluracil and uracil mispaired with guanine can be processed by ncMMR and long-patch BER with concomitant removal of distant 5mC residues. Furthermore, the presence of multiple mispairs in the same MMR nick/mismatch recognition region together with BER-mediated nick formation promotes proficient ncMMR resulting in the reactivation of an epigenetically silenced reporter gene in murine cells. These findings suggest cooperation between BER and ncMMR in the removal of multiple mismatches that might occur in mammalian cells during ADDM. Oxford University Press 2016-05-05 2016-02-03 /pmc/articles/PMC4856981/ /pubmed/26843430 http://dx.doi.org/10.1093/nar/gkw059 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication Grin, Inga Ishchenko, Alexander A. An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title | An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title_full | An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title_fullStr | An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title_full_unstemmed | An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title_short | An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation |
title_sort | interplay of the base excision repair and mismatch repair pathways in active dna demethylation |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856981/ https://www.ncbi.nlm.nih.gov/pubmed/26843430 http://dx.doi.org/10.1093/nar/gkw059 |
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