小柯机器人

加拿大多伦多大学Alberto Martin团队近日取得一项新成果。他们揭示FAM72A 拮抗尿嘧啶 DNA 糖基化酶 2 (UNG2) 以促进抗体成熟过程中的诱变修复。这一研究成果发表在2021年11月24日出版的国际学术期刊《自然》上。

他们使用全基因组 CRISPR 筛选显示 FAM72A 是脱氧尿嘧啶易错加工的主要决定因素。来自 Fam72a-/- 小鼠的 Fam72a 缺陷型 CH12F3-2 B 细胞和原代 B 细胞表现出免疫球蛋白和 Bcl6 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降低。 Fam72a-/- 小鼠 B 细胞中的体细胞超突变谱与在UNG2缺陷小鼠中观察到的相反，这表明 UNG2 在 FAM72A 缺陷细胞中过度活跃。

事实上，FAM72A 与 UNG2 结合，导致细胞周期 G1 期 UNG2 蛋白水平降低，与激活诱导的胞苷脱氨酶 (AID)活性峰值一致。因此，FAM72A 会导致 U·G 错配持续进入 S 阶段，导致通过错配修复进行易错修复加工。通过禁用通常从 DNA 中有效去除脱氧尿嘧啶的 DNA 修复途径，FAM72A 使 AID 能够充分发挥其对抗体成熟的影响。这项工作对肿瘤有影响，因为在许多肿瘤中观察到的 FAM72A 过表达可以促进诱变。

据了解，AID催化免疫球蛋白基因内的脱氧胞苷脱氨为脱氧尿嘧啶，从而诱导体细胞超突变和类别转换重组。AID 产生的脱氧尿嘧啶被颠覆的碱基切除和错配修复途径识别和加工，确保在 B 细胞中产生诱变结果。然而，为什么这些 DNA 修复途径不能准确修复 AID 诱导的病变仍然未知。

附：英文原文

Title: FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation

Author: Feng, Yuqing, Li, Conglei, Stewart, Jessica A., Barbulescu, Philip, Desivo, No Seija, lvarez-Quiln, Alejandro, Pezo, Rossanna C., Perera, Madusha L. W., Chan, Katherine, Tong, Amy Hin Yan, Mohamad-Ramshan, Rukshana, Berru, Maribel, Nakib, Diana, Li, Gavin, Kardar, Gholam Ali, Carlyle, James R., Moffat, Jason, Durocher, Daniel, Di Noia, Javier M., Bhagwat, Ashok S., Martin, Alberto

Issue&Volume: 2021-11-24

Abstract: Activation-induced cytidine deaminase (AID) catalyses the deamination of deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic hypermutation and class-switch recombination1,2. AID-generated deoxyuracils are recognized and processed by subverted base-excision and mismatch repair pathways that ensure a mutagenic outcome in B cells3,4,5,6. 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)7, 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 cancers8 could promote mutagenesis.

DOI: 10.1038/s41586-021-04144-4

Source: https://www.nature.com/articles/s41586-021-04144-4

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