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Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification

Uracil arises in cellular DNA by cytosine (C) deamination and erroneous replicative incorporation of deoxyuridine monophosphate opposite adenine. The former generates C → thymine transition mutations if uracil is not removed by uracil-DNA glycosylase (UDG) and replaced by C by the base excision repa...

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Autores principales: Alexeeva, Marina, Moen, Marivi Nabong, Xu, Xiang Ming, Rasmussen, Anette, Leiros, Ingar, Kirpekar, Finn, Klungland, Arne, Alsøe, Lene, Nilsen, Hilde, Bjelland, Svein
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730318/
https://www.ncbi.nlm.nih.gov/pubmed/35003074
http://dx.doi.org/10.3389/fimmu.2021.762032
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author Alexeeva, Marina
Moen, Marivi Nabong
Xu, Xiang Ming
Rasmussen, Anette
Leiros, Ingar
Kirpekar, Finn
Klungland, Arne
Alsøe, Lene
Nilsen, Hilde
Bjelland, Svein
author_facet Alexeeva, Marina
Moen, Marivi Nabong
Xu, Xiang Ming
Rasmussen, Anette
Leiros, Ingar
Kirpekar, Finn
Klungland, Arne
Alsøe, Lene
Nilsen, Hilde
Bjelland, Svein
author_sort Alexeeva, Marina
collection PubMed
description Uracil arises in cellular DNA by cytosine (C) deamination and erroneous replicative incorporation of deoxyuridine monophosphate opposite adenine. The former generates C → thymine transition mutations if uracil is not removed by uracil-DNA glycosylase (UDG) and replaced by C by the base excision repair (BER) pathway. The primary human UDG is hUNG. During immunoglobulin gene diversification in activated B cells, targeted cytosine deamination by activation-induced cytidine deaminase followed by uracil excision by hUNG is important for class switch recombination (CSR) and somatic hypermutation by providing the substrate for DNA double-strand breaks and mutagenesis, respectively. However, considerable uncertainty remains regarding the mechanisms leading to DNA incision following uracil excision: based on the general BER scheme, apurinic/apyrimidinic (AP) endonuclease (APE1 and/or APE2) is believed to generate the strand break by incising the AP site generated by hUNG. We report here that hUNG may incise the DNA backbone subsequent to uracil excision resulting in a 3´-α,β-unsaturated aldehyde designated uracil-DNA incision product (UIP), and a 5´-phosphate. The formation of UIP accords with an elimination (E2) reaction where deprotonation of C2´ occurs via the formation of a C1´ enolate intermediate. UIP is removed from the 3´-end by hAPE1. This shows that the first two steps in uracil BER can be performed by hUNG, which might explain the significant residual CSR activity in cells deficient in APE1 and APE2.
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spelling pubmed-87303182022-01-06 Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification Alexeeva, Marina Moen, Marivi Nabong Xu, Xiang Ming Rasmussen, Anette Leiros, Ingar Kirpekar, Finn Klungland, Arne Alsøe, Lene Nilsen, Hilde Bjelland, Svein Front Immunol Immunology Uracil arises in cellular DNA by cytosine (C) deamination and erroneous replicative incorporation of deoxyuridine monophosphate opposite adenine. The former generates C → thymine transition mutations if uracil is not removed by uracil-DNA glycosylase (UDG) and replaced by C by the base excision repair (BER) pathway. The primary human UDG is hUNG. During immunoglobulin gene diversification in activated B cells, targeted cytosine deamination by activation-induced cytidine deaminase followed by uracil excision by hUNG is important for class switch recombination (CSR) and somatic hypermutation by providing the substrate for DNA double-strand breaks and mutagenesis, respectively. However, considerable uncertainty remains regarding the mechanisms leading to DNA incision following uracil excision: based on the general BER scheme, apurinic/apyrimidinic (AP) endonuclease (APE1 and/or APE2) is believed to generate the strand break by incising the AP site generated by hUNG. We report here that hUNG may incise the DNA backbone subsequent to uracil excision resulting in a 3´-α,β-unsaturated aldehyde designated uracil-DNA incision product (UIP), and a 5´-phosphate. The formation of UIP accords with an elimination (E2) reaction where deprotonation of C2´ occurs via the formation of a C1´ enolate intermediate. UIP is removed from the 3´-end by hAPE1. This shows that the first two steps in uracil BER can be performed by hUNG, which might explain the significant residual CSR activity in cells deficient in APE1 and APE2. Frontiers Media S.A. 2021-12-22 /pmc/articles/PMC8730318/ /pubmed/35003074 http://dx.doi.org/10.3389/fimmu.2021.762032 Text en Copyright © 2021 Alexeeva, Moen, Xu, Rasmussen, Leiros, Kirpekar, Klungland, Alsøe, Nilsen and Bjelland https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Alexeeva, Marina
Moen, Marivi Nabong
Xu, Xiang Ming
Rasmussen, Anette
Leiros, Ingar
Kirpekar, Finn
Klungland, Arne
Alsøe, Lene
Nilsen, Hilde
Bjelland, Svein
Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title_full Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title_fullStr Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title_full_unstemmed Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title_short Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification
title_sort intrinsic strand-incision activity of human ung: implications for nick generation in immunoglobulin gene diversification
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730318/
https://www.ncbi.nlm.nih.gov/pubmed/35003074
http://dx.doi.org/10.3389/fimmu.2021.762032
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