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| Subject Categories: Genome Stability & Dynamics | Immunology |
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| The EMBO Journal
(2006) 25, 585–595, doi:10.1038/sj.emboj.7600939 Published online 12 January 2006 |
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| SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation versus repair |
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| Javier M Di Noia, Cristina Rada and Michael S Neuberger |
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Medical Research Council Laboratory of Molecular Biology, Cambridge, UK To whom correspondence should be addressed Javier M Di Noia, Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Tel.: +44 1223 248011; Fax: +44 1223 412178; E-mail: jmdinoia@mrc-lmb.cam.ac.uk Received 29 September 2005; Accepted 9 December 2005; Published online 12 January 2006. |
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| Abstract |
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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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| Keywords: antibody diversification, DNA deamination, SMUG1, UNG, uracil-DNA glycosylase |
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