University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Australia.
University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Australia.
Mutat Res. 2020 May-Dec;821:111695. doi: 10.1016/j.mrfmmm.2020.111695. Epub 2020 Mar 6.
The protein defective in the human genetic disorder ataxia-telangiectasia, ATM, plays a central role in responding to DNA double strand breaks and other lesions to protect the genome against DNA damage and in this way minimize the risk of mutations that can lead to abnormal cellular behaviour. Its function in normal cells is to protect the cell against genotoxic stress but inadvertently it can assist cancer cells by providing resistance against chemotherapeutic agents and thus favouring tumour growth and survival. However, it is now evident that ATM also functions in a DNA damage-independent fashion to protect the cell against other forms of stress such as oxidative and nutrient stress and this non-canonical mechanism may also be relevant to cancer susceptibility in individuals who lack a functional ATM gene. Thus the use of ATM inhibitors to combat resistance in tumours may extend beyond a role for this protein in the DNA damage response. Here, we provide some background on ATM and its activation and investigate the efficacy of ATM inhibitors in treating cancer.
在人类遗传疾病共济失调毛细血管扩张症中出现缺陷的蛋白质 ATM，在应对 DNA 双链断裂和其他损伤方面发挥着核心作用，以保护基因组免受 DNA 损伤，并以此最大限度地降低可能导致异常细胞行为的突变风险。其在正常细胞中的功能是保护细胞免受基因毒性应激，但它会无意中通过提供对化疗药物的抗性来帮助癌细胞，从而促进肿瘤生长和存活。然而，现在显然 ATM 还以独立于 DNA 损伤的方式发挥作用，以保护细胞免受其他形式的应激，如氧化应激和营养应激，这种非典型机制也可能与缺乏功能性 ATM 基因的个体的癌症易感性有关。因此，使用 ATM 抑制剂来对抗肿瘤的耐药性可能超出了该蛋白在 DNA 损伤反应中的作用。在这里，我们提供了一些关于 ATM 及其激活的背景信息，并研究了 ATM 抑制剂在治疗癌症方面的疗效。
