Uracil-DNA glycosylase UNG1 isoform variant supports class switch recombination and repairs nuclear genomic uracil
Uracil-DNA glycosylase UNG1 isoform variant supports class switch recombination and repairs nuclear genomic uracil
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DOI：
10.1093/nar/gkz145
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发表时间：
2019-05-21
影响因子：
14.9
通讯作者：
Kavli, Bodil
中科院分区：
文献类型：
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作者：
Sarno, Antonio;Lundbaek, Marie;Kavli, Bodil
UNG 是哺乳动物细胞中主要的尿嘧啶-DNA 糖基化酶，参与基因组尿嘧啶的无错碱基切除修复和抗体基因的诱变尿嘧啶加工。然而，目前对 UNG 在这些不同过程中的监管尚不清楚。 UNG 基因编码两种亚型 UNG1 和 UNG2，每种亚型都具有独特的 N 末端，分别介导易位至线粒体和细胞核。尽管缺乏单独研究它们的模型，但每种亚型的严格亚细胞定位已被广泛接受。为了确定每种亚型的作用，我们生成并表征了几种 UNG 亚型特异性小鼠和人类细胞系。我们发现了一种独特的 UNG1 同工型变体，该变体针对细胞核，支持抗体类别转换并修复基因组尿嘧啶。我们认为，与 UNG2 相比，核 UNG1 变体缺乏 PCNA 结合基序，可能通过其结合 RPA 的能力专门作用于 ssDNA。 RPA 包被的 ssDNA 区域包括转录的抗体基因（AID 脱氨基的靶标）和移动复制叉前面的区域。我们的研究结果为 UNG 同工型在适应性免疫和 DNA 修复中的功能提供了新的见解。
UNG is the major uracil-DNA glycosylase in mammalian cells and is involved in both error-free base excision repair of genomic uracil and mutagenic uracil-processing at the antibody genes. However, the regulation of UNG in these different processes is currently not well understood. The UNG gene encodes two isoforms, UNG1 and UNG2, each possessing unique N-termini that mediate translocation to the mitochondria and the nucleus, respectively. A strict subcellular localization of each isoform has been widely accepted despite a lack of models to study them individually. To determine the roles of each isoform, we generated and characterized several UNG isoform-specific mouse and human cell lines. We identified a distinct UNG1 isoform variant that is targeted to the cell nucleus where it supports antibody class switching and repairs genomic uracil. We propose that the nuclear UNG1 variant, which in contrast to UNG2 lacks a PCNA-binding motif, may be specialized to act on ssDNA through its ability to bind RPA. RPA-coated ssDNA regions include both transcribed antibody genes that are targets for deamination by AID and regions in front of the moving replication forks. Our findings provide new insights into the function of UNG isoforms in adaptive immunity and DNA repair.