丹麦哥本哈根大学Claus S. Sørensen研究团队发现癌细胞利用自身产生的DNA断裂，来避免由基因毒性带来的生长限制。该项研究成果发表在2022年4月29日出版的《科学》上。

研究人员发现癌细胞在放疗期间通过可逆地增加全基因组DNA断裂来维持活力，从而限制有丝分裂进程的提前开启。研究人员发现半胱天冬酶激活的DNase(CAD)是造成特异位点从头DNA损伤的核酸酶，这些位点靠近染色质修饰CCCTC结合因子(CTCF)位点。CAD核酸酶活性由DNA损伤反应激酶的磷酸化调控，与半胱天冬酶的活性无关。

反过来，CAD活性的丧失会损害细胞命运决定，使癌细胞容易受到辐射诱导DNA双链断裂的影响。该研究发现癌症可选择性适应环境，即肿瘤细胞通过调节DNA断裂来限制治疗引起DNA损伤的有害影响。

据介绍，诸如放射类基因毒性疗法是一线癌症治疗方法，但容易导致肿瘤复发性获得性耐药的产生。

附：英文原文

Title: Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress

Author: Brian D. Larsen, Jan Benada, Philip Yuk Kwong Yung, Ryan A. V. Bell, George Pappas, Vaclav Urban, Johanna K. Ahlskog, Tia T. Kuo, Pavel Janscak, Lynn A. Megeney, Simon J. Elssser, Jiri Bartek, Claus S. Srensen

Issue&Volume: 2022-04-29

Abstract: Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.

DOI: abi6378

Source: https://www.science.org/doi/10.1126/science.abi6378