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Impact of Chk1 dosage on somatic hypermutation in vivo
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2021-05-27 , DOI: 10.1111/imcb.12480
Amanda Bello 1 , Berit Jungnickel 1
Affiliation  

Checkpoint signaling in the context of a functional DNA damage response is crucial for the prevention of oncogenic transformation of cells. Our immune system, though, takes the risk of attenuated checkpoint responses during immunoglobulin diversification. B cells undergo continuous DNA damage and error-prone repair of their immunoglobulin genes during the process of somatic hypermutation. An accompanying attenuation of the DNA damage response via the ATR–Chk1 axis in B cells is believed to allow for a better DNA damage tolerance and for evasion of apoptosis, so as to ensure mutations to be passed on. We sought to determine whether the downregulation of Chk1 could also directly influence the process of hypermutation in vivo by altering the relative activity of error-prone DNA repair pathways. We analyzed the humoral response and the hypermutation process in mice whose B cells express reduced levels of the Chk1 protein. We found that Chk1 heterozygosity limits the accumulation of mutations in the immunoglobulin loci, likely by impacting on the survival of B cells as they accumulate DNA damage. Nevertheless, we unveiled an unanticipated role for Chk1 downregulation in favoring A/T mutagenesis at the antibody-variable regions during hypermutation. Even though immunoglobulin mutagenesis was found to be reduced, Chk1 signaling attenuation allows for sustained mutagenesis outside the immunoglobulin loci. Our study thus reveals that a proper Chk1 dosage is crucial for adequate somatic hypermutation in B cells.

中文翻译:

Chk1剂量对体内体细胞超突变的影响

功能性 DNA 损伤反应背景下的检查点信号传导对于防止细胞致癌转化至关重要。然而,我们的免疫系统在免疫球蛋白多样化过程中冒着检查点反应减弱的风险。B 细胞在体细胞超突变过程中经历持续的 DNA 损伤和免疫球蛋白基因的易错修复。通过 B 细胞中的 ATR-Chk1 轴伴随的 DNA 损伤反应减弱被认为允许更好的 DNA 损伤耐受性和逃避细胞凋亡,从而确保突变得以传递。我们试图确定 Chk1 的下调是否也可以直接影响体内超突变过程通过改变容易出错的 DNA 修复途径的相对活性。我们分析了 B 细胞表达水平降低的 Chk1 蛋白的小鼠的体液反应和超突变过程。我们发现Chk1杂合性限制了免疫球蛋白基因座中突变的积累,这可能是因为 B 细胞积累 DNA 损伤时会影响它们的存活。尽管如此,我们揭示了 Chk1 下调在超突变期间有利于抗体可变区的 A/T 突变的意外作用。尽管发现免疫球蛋白诱变减少,但 Chk1 信号减弱允许免疫球蛋白位点外的持续诱变。因此,我们的研究表明,适当的 Chk1 剂量对于 B 细胞中足够的体细胞超突变至关重要。
更新日期:2021-05-27
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