Di Noia Javier M, Rada Cristina, Neuberger Michael S
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
EMBO J. 2006 Feb 8;25(3):585-95. doi: 10.1038/sj.emboj.7600939. Epub 2006 Jan 12.
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.
哺乳动物体内含有多种能够从DNA中切除尿嘧啶的酶，尽管它们各自独特的生理作用仍不明确。其中一种酶（尿嘧啶-DNA糖基化酶，UNG）在抗体基因多样化过程中发挥着关键作用，因为仅UNG缺陷就足以扰乱这一过程。在此，我们表明UNG的这种独特需求并不反映其他糖基化酶无法作用于U:G损伤这一事实。如果过表达，单链特异性尿嘧啶-DNA糖基化酶1（SMUG1）可以部分替代UNG来协助抗体多样化，这可通过其对体细胞高频突变模式的影响（在DT40 B细胞和小鼠中）以及SMUG转基因msh2 -/- ung -/-小鼠中同种型转换的恢复来判断。然而，SMUG1在抗体多样化过程中几乎没有天然作用，原因如下：（i）它在B细胞激活过程中的表达逐渐减少；（ii）即使过表达，SMUG1似乎更倾向于尿嘧啶损伤的常规修复而非协助多样化。UNG与过表达的SMUG1在抗体多样化和U:G损伤的非诱变修复之间平衡方面的差异，可能反映了UNG（而非SMUG1）与DNA复制位点的关联。
