Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase
Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase
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DOI：
10.1073/pnas.1402391111
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
A. Yousif;A. Stanlie;S. Mondal;T. Honjo;N. Begum
中科院分区：
文献类型：
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作者：
A. Yousif;A. Stanlie;S. Mondal;T. Honjo;N. Begum
意义 尿嘧啶 DNA 糖基化酶 (UNG) 被认为是类转换重组 (CSR) 和体细胞超突变 (SHM) 所需的关键碱基切除修复蛋白。另一方面，它在企业社会责任和安全健康管理中的确切功能是极具争议性和难以捉摸的。在这里，我们表明，UNG 通过招募忠实的 DNA 修复复合物来抑制 S 区 SHM (s-SHM)，并且在缺乏 UNG 的情况下，招募容易出错的修复复合物，从而诱导 s-SHM 覆盖。此外，UNG 通过调节 S-S 突触和 DNA 末端修复来促进活化诱导的胞苷脱氨酶诱导的 CSR。有趣的是，UNG 的酶活性对于 s-SHM 抑制和 CSR 促进是可有可无的。激活诱导的胞苷脱氨酶 (AID) 对于 V 区 SHM 和 S 区 SHM (s-SHM) 中的类别转换重组 (CSR) 和体细胞超突变 (SHM) 至关重要。尿嘧啶 DNA 糖基化酶 (UNG) 是碱基切除修复 (BER) 复合物的成员，是 CSR 所必需的。然而，引人注目的是，UNG 缺乏会导致 SHM 增强，这表明 UNG 的不同功能参与了 SHM 和 CSR。在这里，我们表明 UNG 的非规范支架功能对 s-SHM 负调节，对 CSR 正调节。 UNG 的 s-SHM 抑制功能归因于在切割的 DNA 基因座处招募忠实的 BER 成分，并与容易出错的聚合酶竞争。相比之下，UNG 的 CSR 促进功能通过招募 p53 结合蛋白 1 和 DNA 依赖性蛋白激酶（催化亚基）来增强 AID 依赖性 S-S 突触形成。 UNG 的几种催化缺失突变体区分了 CSR 促进活性和 s-SHM 抑制活性。总而言之，UNG 的非规范功能调节 AID 诱导的 DNA 切割后的步骤：s-SHM 中的易错修复抑制和 CSR 中的末端连接促进。
Significance Uracil DNA glycosylase (UNG) has been known as a critical base excision repair protein required for class switch recombination (CSR) and somatic hypermutation (SHM). On the other hand, its precise function in both CSR and SHM is extremely debatable and elusive. Here, we showed that UNG suppresses S region SHM (s-SHM) by recruiting the faithful DNA repair complex and, in the absence of UNG, the error-prone repair complex that induces s-SHM overrides. Moreover, UNG promotes activation-induced cytidine deaminase-induced CSR by regulating S-S synapse and DNA end repair. Interestingly, the enzymatic activity of UNG is dispensable for s-SHM suppression and CSR promotion. Activation-induced cytidine deaminase (AID) is essential to class-switch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHM and CSR. Here, we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNA-dependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: error-prone repair suppression in s-SHM and end-joining promotion in CSR.