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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...

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Autores principales: Duan, Mingrui, Sivapragasam, Smitha, Antony, Jacob S, Ulibarri, Jenna, Hinz, John M, Poon, Gregory MK, Wyrick, John J, Mao, Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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.
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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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