FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation.
FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation.
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DOI：
10.1038/s41586-021-04144-4
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发表时间：
2021-12
期刊：
影响因子：
64.8
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中科院分区：
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激活诱导的胞苷脱氨酶（AID）催化免疫球蛋白基因内脱氧胞苷脱氨基为脱氧尿嘧啶，以诱导体细胞超突变和类别转换重组。艾滋病产生的脱氧尿嘧啶被识别和处理的破坏碱基切除和错配修复途径，确保在B细胞的诱变结果。然而，为什么这些DNA修复途径不能准确修复艾滋病诱导的病变仍然未知。在这里，使用全基因组CRISPR筛选，我们表明FAM 72 A是脱氧尿嘧啶易错加工的主要决定因素。来自Fam 72 a −/−小鼠的Fam 72 a缺陷型CH 12 F3 -2 B细胞和原代B细胞表现出免疫球蛋白和Bcl 6基因的类别转换重组和体细胞超突变频率降低，以及全基因组脱氧尿嘧啶减少。来自Fam 72 a −/−小鼠的B细胞中的体细胞超突变谱与在尿嘧啶DNA糖基化酶2（UNG 2）缺陷小鼠中观察到的相反，这表明UNG 2在FAM 72 A缺陷细胞中过度活跃。事实上，FAM 72 A与UNG 2结合，导致细胞周期G1期UNG 2蛋白水平降低，与峰值AID活性一致。因此，FAM 72 A导致U·G错配持续到S期，导致通过错配修复进行易于出错的处理。通过使通常有效地从DNA中去除脱氧尿嘧啶的DNA修复途径失效，FAM 72 A使AID能够对抗体成熟发挥其全部作用。这项工作在癌症中有意义，因为在许多癌症中观察到的FAM 72 A的过表达可能会促进诱变。
Activation-induced cytidine deaminase (AID) catalyses the deamination of deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic hypermutation and class-switch recombination. AID-generated deoxyuracils are recognized and processed by subverted base-excision and mismatch repair pathways that ensure a mutagenic outcome in B cells. However, why these DNA repair pathways do not accurately repair AID-induced lesions remains unknown. Here, using a genome-wide CRISPR screen, we show that FAM72A is a major determinant for the error-prone processing of deoxyuracils. Fam72a-deficient CH12F3–2 B cells and primary B cells from Fam72a−/− mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, and reduced genome-wide deoxyuracils. The somatic hypermutation spectrum in B cells from Fam72a−/− mice is opposite to that observed in mice deficient in uracil DNA glycosylase 2 (UNG2), which suggests that UNG2 is hyperactive in FAM72A-deficient cells. Indeed, FAM72A binds to UNG2, resulting in reduced levels of UNG2 protein in the G1 phase of the cell cycle, coinciding with peak AID activity. FAM72A therefore causes U·G mispairs to persist into S phase, leading to error-prone processing by mismatch repair. By disabling the DNA repair pathways that normally efficiently remove deoxyuracils from DNA, FAM72A enables AID to exert its full effects on antibody maturation. This work has implications in cancer, as the overexpression of FAM72A that is observed in many cancers could promote mutagenesis.
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DOI：
10.1084/jem.187.11.1745
发表时间：
1998-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Phung QH;Winter DB;Cranston A;Tarone RE;Bohr VA;Fishel R;Gearhart PJ
通讯作者：
Gearhart PJ
影响因子：
9.2
作者：
Rada, C;Williams, GT;Neuberger, MS
通讯作者：
Neuberger, MS
影响因子：
64.8
作者：
Liu, Man;Duke, Jamie L.;Schatz, David G.
通讯作者：
Schatz, David G.
影响因子：
14.9
作者：
Sarno, Antonio;Lundbaek, Marie;Kavli, Bodil
通讯作者：
Kavli, Bodil
影响因子：
4.8
作者：
Krusong, K;Carpenter, EP;Baldwin, GS
通讯作者：
Baldwin, GS