Journal
EMBO JOURNAL
Volume 25, Issue 3, Pages 585-595Publisher
WILEY
DOI: 10.1038/sj.emboj.7600939
Keywords
antibody diversification; DNA deamination; SMUG1; UNG; uracil-DNA glycosylase
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Funding
- Medical Research Council [MC_U105178806] Funding Source: Medline
- Medical Research Council [MC_U105178806] Funding Source: researchfish
- MRC [MC_U105178806] Funding Source: UKRI
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Mammals harbour multiple enzymes capable of excising uracil from DNA, although their distinct physiological roles remain uncertain. One of them (UNG) plays a critical role in antibody gene diversification, as UNG deficiency alone is sufficient to perturb the process. Here, we show this unique requirement for UNG does not reflect the fact that other glycosylases are unable to access the U: G lesion. SMUG1, if overexpressed, can partially substitute for UNG to assist antibody diversification as judged by its effect on somatic hypermutation patterns ( in both DT40 B cells and mice) as well as a restoration of isotype switching in SMUG-transgenic msh2(-/-) ung(-/-) mice. However, SMUG1 plays little natural role in antibody diversification because (i) it is diminishingly expressed during B-cell activation and (ii) even if overexpressed, SMUG1 more appears to favour conventional repair of the uracil lesion than assist diversification. The distinction between UNG and overexpressed SMUG1 regarding the balance between antibody diversification and non-mutagenic repair of the U: G lesion could reflect the association of UNG ( but not SMUG1) with sites of DNA replication.
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