Ueno Sayaka, Sudo Tamotsu, Hirasawa Akira
Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji-cho, Akashi-shi 673-8558, Japan.
Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Int J Mol Sci. 2022 Jan 4;23(1):523. doi: 10.3390/ijms23010523.
Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the gene, function of ATM kinase, clinical significance of germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.
共济失调毛细血管扩张症突变基因（ATM）作为DNA损伤和细胞应激反应的关键启动者和协调者发挥作用。ATM信号通路包含许多下游靶点，这些靶点调节多种重要的细胞过程，包括DNA损伤修复、细胞凋亡、细胞周期停滞、氧化感应和细胞增殖。在过去几十年中，已报道了种系致病变体与癌症风险之间的关联，尤其是乳腺癌和胰腺癌。此外，鉴于ATM在修复双链断裂中起关键作用，抑制其他DNA修复途径可能是一种合成致死方法。基于这一原理，目前正在对几种DNA损伤反应抑制剂在ATM缺陷型癌症中进行测试。在这篇综述中，我们讨论了与该基因结构、ATM激酶功能、遗传性癌症患者种系致病变体的临床意义以及为癌症患者靶向ATM的持续努力相关的现有知识。
