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dc.contributor.authorAlexeeva, Marina
dc.contributor.authorMoen, Marivi Nabong
dc.contributor.authorXu, Xiang Ming
dc.contributor.authorRasmussen, Anette
dc.contributor.authorLeiros, Ingar
dc.contributor.authorKirpekar, Finn
dc.contributor.authorKlungland, Arne
dc.contributor.authorAlsøe, Lene
dc.contributor.authorNilsen, Hilde
dc.contributor.authorBjelland, Svein
dc.date.accessioned2022-02-14T13:01:42Z
dc.date.available2022-02-14T13:01:42Z
dc.date.issued2021-12-22
dc.description.abstractUracil 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´-a,b-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.en_US
dc.identifier.citationAlexeeva M, Moen M, Xu XM, Rasmussen A, Leiros I, Kirpekar F, Klungland A, Alsøe L, Nilsen H, Bjelland S. Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification. Frontiers in Immunology. 2021;12en_US
dc.identifier.cristinIDFRIDAID 1979463
dc.identifier.doi10.3389/fimmu.2021.762032
dc.identifier.issn1664-3224
dc.identifier.urihttps://hdl.handle.net/10037/24044
dc.language.isoengen_US
dc.publisherFrontiers Mediaen_US
dc.relation.journalFrontiers in Immunology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.titleIntrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversificationen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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