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FATC 结构域缺失破坏 ATM 蛋白稳定性，阻断淋巴细胞发育，并促进淋巴瘤发生。

FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

机构信息

Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032.

Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032.

出版信息

J Immunol. 2021 Mar 15;206(6):1228-1239. doi: 10.4049/jimmunol.2000967. Epub 2021 Feb 3.

DOI:10.4049/jimmunol.2000967
PMID:33536256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9305077/
Abstract

Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (⁠ ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in ⁠ ⁠ mice compared with ⁠ ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

摘要

共济失调毛细血管扩张突变（ATM）激酶是 DNA 损伤反应的主要调节因子，ATM 的缺失导致原发性免疫缺陷，并大大增加了淋巴恶性肿瘤的风险。FATC 结构域在磷脂酰肌醇-3-激酶相关蛋白激酶（PIKKs）中保守。FATC 结构域（R3047X）截断突变选择性地损害了细胞游离试验中活性氧诱导的 ATM 激活。在本文中，我们表明，在小鼠模型中，敲入 ATM-R3057X 突变（⁠ ⁠，对应于人 ATM 中的 R3047X）严重损害 ATM 蛋白稳定性，并导致 T 细胞发育缺陷、B 细胞 Ig 类转换重组缺陷和类似于 ATM 缺失的不育症。残留的 ATM-R3057X 蛋白保留了最小但功能上可测量的 DNA 损伤诱导的检查点激活，并与 ⁠ ⁠相比，显著延迟了 ⁠ ⁠小鼠的淋巴瘤发生。这些结果共同支持 FATC 结构域在 ATM 蛋白稳定性中的生理作用，并表明最小残留的 ATM-R3057X 蛋白的存在可以预防生长迟缓并延迟肿瘤发生，而无需恢复淋巴细胞发育和生育能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/b5c41e852469/nihms-1661647-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/c7df869f202e/nihms-1661647-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/9a863906e81b/nihms-1661647-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/ff20a264961d/nihms-1661647-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/84f0ea83aaf5/nihms-1661647-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/faa7460d9bba/nihms-1661647-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/b5c41e852469/nihms-1661647-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/c7df869f202e/nihms-1661647-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/9a863906e81b/nihms-1661647-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/ff20a264961d/nihms-1661647-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/84f0ea83aaf5/nihms-1661647-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/faa7460d9bba/nihms-1661647-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7141/9305077/b5c41e852469/nihms-1661647-f0006.jpg

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2
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DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination.
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