小柯机器人

Fam72a在抗体多样化过程中增强易错的DNA修复
2021-11-28 13:55

法国国家卫生研究院Bernardo Reina-San-Martin团队发现,Fam72a在抗体多样化过程中增强易错的DNA修复。相关论文于2021年11月24日在线发表在《自然》杂志上。

研究人员表示,高效的体液反应依赖于DNA损伤、诱变和易错的DNA修复。B细胞受体的多样化通过体细胞高突变和类开关重组开始,由激活诱导的胞苷脱氨酶(AID)介导的DNA胞苷脱氨,以及随后由尿嘧啶DNA糖基化酶(UNG)和错配修复蛋白切除产生的尿嘧啶。尽管DNA中出现的尿嘧啶被准确地修复,但在体细胞超突变和类别转换重组的背景下,这些途径是如何被合用来产生突变和双链DNA断裂的,尚不清楚。
 
研究人员对参与类别转换重组的基因进行了全基因组CRISPR-Cas9敲除筛选,并确定了FAM72A,一种与UNG(UNG2)的核异构体相互作用并在几种癌症中过表达的蛋白质。结果表明,FAM72A-UNG2的相互作用控制着UNG2的水平,由于UNG2的上调,类别转换重组在Fam72a-/-B细胞中出现缺陷。此外,结果显示体细胞超突变在Fam72a-/-B细胞中减少,并且在UNG2上调后其模式发生倾斜。
 
研究结果与一个模型一致,即FAM72A与UNG2相互作用,通过触发其降解来控制其生理水平,调节尿嘧啶切除的水平,从而调节易错和无错DNA修复之间的平衡。这些发现对肿瘤发生有潜在的影响,因为Fam72a的过量表达所介导的UNG2水平的降低会使平衡转向诱变性DNA修复,使细胞更容易获得突变。
 
附:英文原文

Title: Fam72a enforces error-prone DNA repair during antibody diversification

Author: Rogier, Mlanie, Moritz, Jacques, Robert, Isabelle, Lescale, Chlo, Heyer, Vincent, Abello, Arthur, Martin, Ophlie, Capitani, Katia, Thomas, Morgane, Thomas-Claudepierre, Anne-Sophie, Laffleur, Brice, Jouan, Florence, Pinaud, Eric, Tarte, Karin, Cogn, Michel, Conticello, Silvestro G., Soutoglou, Evi, Deriano, Ludovic, Reina-San-Martin, Bernardo

Issue&Volume: 2021-11-24

Abstract: Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. Diversification of B cell receptors through somatic hypermutation and class-switch recombination are initiated by cytidine deamination in DNA mediated by activation-induced cytidine deaminase (AID)1 and by the subsequent excision of the resulting uracils by uracil DNA glycosylase (UNG) and by mismatch repair proteins1,2,3. Although uracils arising in DNA are accurately repaired1,2,3,4, how these pathways are co-opted to generate mutations and double-strand DNA breaks in the context of somatic hypermutation and class-switch recombination is unknown1,2,3. Here we performed a genome-wide CRISPR–Cas9 knockout screen for genes involved in class-switch recombination and identified FAM72A, a protein that interacts with the nuclear isoform of UNG (UNG2)5 and is overexpressed in several cancers5. We show that the FAM72A–UNG2 interaction controls the levels of UNG2 and that class-switch recombination is defective in Fam72a/ B cells due to the upregulation of UNG2. Moreover, we show that somatic hypermutation is reduced in Fam72a/ B cells and that its pattern is skewed upon upregulation of UNG2. Our results are consistent with a model in which FAM72A interacts with UNG2 to control its physiological level by triggering its degradation, regulating the level of uracil excision and thus the balance between error-prone and error-free DNA repair. Our findings have potential implications for tumorigenesis, as reduced levels of UNG2 mediated by overexpression of Fam72a would shift the balance towards mutagenic DNA repair, rendering cells more prone to acquire mutations.

DOI: 10.1038/s41586-021-04093-y

Source: https://www.nature.com/articles/s41586-021-04093-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0