Free Radical Research ( IF 3.3 ) Pub Date : 2021-01-27 , DOI: 10.1080/10715762.2021.1876853 Somnath Ghosh 1 , Anu Ghosh 1, 2
Abstract
Cellular responses to DNA damage are fundamental to preserve genomic integrity during various endogenous and exogenous stresses. Following radiation therapy and chemotherapy, this DNA damage response (DDR) also determines development of carcinogenesis and therapeutic outcome. In humans, DNA damage activates a robust network of signal transduction cascades, driven primarily through phosphorylation events. These responses primarily involve two key non-redundant signal transducing proteins of phosphatidylinositol 3-kinase-like (PIKK) family – ATR and ATM, and their downstream kinases (hChk1 and hChk2). They further phosphorylate effectors proteins such as p53, Cdc25A and Cdc25C which function either to activate the DNA damage checkpoints and cell death mechanisms, or DNA repair pathways. Identification of molecular pathways that determine signaling after DNA damage and trigger DNA repair in response to differing types of DNA lesions allows for a far better understanding of the consequences of radiation and chemotherapy on normal and tumor cells. Here we highlight the network of DNA damage response pathways that are activated after treatment with different types of radiation. Further, we discuss regulation of cell cycle checkpoint and DNA repair processes in the context of DDR in response to radiation.
中文翻译:
通过电离辐射激活哺乳动物细胞中的 DNA 损伤反应信号
摘要
细胞对 DNA 损伤的反应是在各种内源性和外源性压力下保持基因组完整性的基础。放疗和化疗后,这种 DNA 损伤反应 (DDR) 也决定了致癌作用的发展和治疗结果。在人类中,DNA 损伤激活了一个强大的信号转导级联网络,主要通过磷酸化事件驱动。这些反应主要涉及磷脂酰肌醇 3 激酶样 (PIKK) 家族的两个关键非冗余信号转导蛋白——ATR 和 ATM,及其下游激酶(hChk1 和 hChk2)。它们进一步磷酸化效应蛋白,如 p53、Cdc25A 和 Cdc25C,其功能是激活 DNA 损伤检查点和细胞死亡机制,或 DNA 修复途径。确定 DNA 损伤后的信号传导和触发 DNA 修复以响应不同类型的 DNA 损伤的分子途径,可以更好地了解放疗和化疗对正常细胞和肿瘤细胞的影响。在这里,我们重点介绍了在用不同类型的辐射治疗后被激活的 DNA 损伤反应通路网络。此外,我们讨论了在 DDR 背景下对辐射的反应调节细胞周期检查点和 DNA 修复过程。