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High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors
DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (T...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970589/ https://www.ncbi.nlm.nih.gov/pubmed/35289750 http://dx.doi.org/10.7554/eLife.73943 |
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author | Duan, Mingrui Sivapragasam, Smitha Antony, Jacob S Ulibarri, Jenna Hinz, John M Poon, Gregory MK Wyrick, John J Mao, Peng |
author_facet | Duan, Mingrui Sivapragasam, Smitha Antony, Jacob S Ulibarri, Jenna Hinz, John M Poon, Gregory MK Wyrick, John J Mao, Peng |
author_sort | Duan, Mingrui |
collection | PubMed |
description | DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), and characterized alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data show that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs ARS binding factor 1 (Abf1) and rDNA enhancer binding protein 1 (Reb1), but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. Repair of ultraviolet (UV) damage by nucleotide excision repair (NER) was also inhibited by TF binding. Interestingly, TF binding inhibits a larger DNA region for NER relative to BER. The observed effects are caused by the TF–DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions. |
format | Online Article Text |
id | pubmed-8970589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-89705892022-04-01 High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors Duan, Mingrui Sivapragasam, Smitha Antony, Jacob S Ulibarri, Jenna Hinz, John M Poon, Gregory MK Wyrick, John J Mao, Peng eLife Cancer Biology DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), and characterized alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data show that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs ARS binding factor 1 (Abf1) and rDNA enhancer binding protein 1 (Reb1), but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. Repair of ultraviolet (UV) damage by nucleotide excision repair (NER) was also inhibited by TF binding. Interestingly, TF binding inhibits a larger DNA region for NER relative to BER. The observed effects are caused by the TF–DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions. eLife Sciences Publications, Ltd 2022-03-15 /pmc/articles/PMC8970589/ /pubmed/35289750 http://dx.doi.org/10.7554/eLife.73943 Text en © 2022, Duan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Duan, Mingrui Sivapragasam, Smitha Antony, Jacob S Ulibarri, Jenna Hinz, John M Poon, Gregory MK Wyrick, John J Mao, Peng High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title | High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title_full | High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title_fullStr | High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title_full_unstemmed | High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title_short | High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors |
title_sort | high-resolution mapping demonstrates inhibition of dna excision repair by transcription factors |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970589/ https://www.ncbi.nlm.nih.gov/pubmed/35289750 http://dx.doi.org/10.7554/eLife.73943 |
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