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Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells

Environmental, endogenous and therapeutic alkylating agents can react with internucleotide phosphate groups in DNA to yield alkyl phosphotriester (PTE) adducts. Alkyl-PTEs are induced at relatively high frequencies and are persistent in mammalian tissues; however, their biological consequences in ma...

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Autores principales: Tan, Ying, Wu, Jiabin, Clabaugh, Garrit, Li, Lin, Du, Hua, Wang, Yinsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997456/
https://www.ncbi.nlm.nih.gov/pubmed/36911626
http://dx.doi.org/10.3390/dna2040016
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author Tan, Ying
Wu, Jiabin
Clabaugh, Garrit
Li, Lin
Du, Hua
Wang, Yinsheng
author_facet Tan, Ying
Wu, Jiabin
Clabaugh, Garrit
Li, Lin
Du, Hua
Wang, Yinsheng
author_sort Tan, Ying
collection PubMed
description Environmental, endogenous and therapeutic alkylating agents can react with internucleotide phosphate groups in DNA to yield alkyl phosphotriester (PTE) adducts. Alkyl-PTEs are induced at relatively high frequencies and are persistent in mammalian tissues; however, their biological consequences in mammalian cells have not been examined. Herein, we assessed how alkyl-PTEs with different alkyl group sizes and stereochemical configurations (S(P) and R(P) diastereomers of Me and nPr) affect the efficiency and fidelity of transcription in mammalian cells. We found that, while the R(P) diastereomer of Me- and nPr-PTEs constituted moderate and strong blockages to transcription, respectively, the S(P) diastereomer of the two lesions did not appreciably perturb transcription efficiency. In addition, none of the four alkyl-PTEs induced mutant transcripts. Furthermore, polymerase η assumed an important role in promoting transcription across the S(P)-Me-PTE, but not any of other three lesions. Loss of other translesion synthesis (TLS) polymerases tested, including Pol κ, Pol ι, Pol ξ and REV1, did not alter the transcription bypass efficiency or mutation frequency for any of the alkyl-PTE lesions. Together, our study provided important new knowledge about the impact of alkyl-PTE lesions on transcription and expanded the substrate pool of Pol η in transcriptional bypass.
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spelling pubmed-99974562023-03-09 Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells Tan, Ying Wu, Jiabin Clabaugh, Garrit Li, Lin Du, Hua Wang, Yinsheng DNA (Basel) Article Environmental, endogenous and therapeutic alkylating agents can react with internucleotide phosphate groups in DNA to yield alkyl phosphotriester (PTE) adducts. Alkyl-PTEs are induced at relatively high frequencies and are persistent in mammalian tissues; however, their biological consequences in mammalian cells have not been examined. Herein, we assessed how alkyl-PTEs with different alkyl group sizes and stereochemical configurations (S(P) and R(P) diastereomers of Me and nPr) affect the efficiency and fidelity of transcription in mammalian cells. We found that, while the R(P) diastereomer of Me- and nPr-PTEs constituted moderate and strong blockages to transcription, respectively, the S(P) diastereomer of the two lesions did not appreciably perturb transcription efficiency. In addition, none of the four alkyl-PTEs induced mutant transcripts. Furthermore, polymerase η assumed an important role in promoting transcription across the S(P)-Me-PTE, but not any of other three lesions. Loss of other translesion synthesis (TLS) polymerases tested, including Pol κ, Pol ι, Pol ξ and REV1, did not alter the transcription bypass efficiency or mutation frequency for any of the alkyl-PTE lesions. Together, our study provided important new knowledge about the impact of alkyl-PTE lesions on transcription and expanded the substrate pool of Pol η in transcriptional bypass. 2022-12 2022-10-05 /pmc/articles/PMC9997456/ /pubmed/36911626 http://dx.doi.org/10.3390/dna2040016 Text en https://creativecommons.org/licenses/by/4.0/This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tan, Ying
Wu, Jiabin
Clabaugh, Garrit
Li, Lin
Du, Hua
Wang, Yinsheng
Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title_full Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title_fullStr Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title_full_unstemmed Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title_short Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells
title_sort size- and stereochemistry-dependent transcriptional bypass of dna alkyl phosphotriester adducts in mammalian cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997456/
https://www.ncbi.nlm.nih.gov/pubmed/36911626
http://dx.doi.org/10.3390/dna2040016
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