文章：

癌细胞利用自我造成的DNA断裂来逃避由基因毒性应激施加的生长限制

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

原文发布日期：2022-04-28

DOI: 10.1126/science.abi6378

类型: Research Article

开放获取: 否

文章简介：

Self-inflicted damage protects tumors

Genotoxic treatments, such as radiation and some chemotherapy drugs, are a mainstay of cancer therapy, but they often fail to fully destroy tumor cells. Normal cells can protect themselves from genotoxic insults by activating the G1 cell cycle checkpoint, but this checkpoint is often dysfunctional in tumors. By contrast, Larsen et al. discovered that tumor cells can activate a nuclease that causes limited induction of DNA breaks at specific sites, which is coordinated with the process of DNA break repair. These self-inflicted DNA breaks trigger the G2 cell cycle checkpoint, preventing tumor cells from cycling and protecting them from death due to treatment-induced DNA damage. —YN

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.

简介翻译： 

自我造成的损伤保护肿瘤

基因毒性治疗，如放射线和一些化疗药物，是癌症治疗的支柱，但它们常常无法完全摧毁肿瘤细胞。正常细胞可以通过激活G1细胞周期检查点来保护自己免受基因毒性损伤，但这个检查点在肿瘤中常常功能失调。相比之下，Larsen等人发现，肿瘤细胞可以激活一种核酸酶，导致在特定位点有限诱导DNA断裂，这与DNA断裂修复过程相协调。这些自我造成的DNA断裂触发G2细胞周期检查点，阻止肿瘤细胞循环，并保护它们免受治疗诱导的DNA损伤导致的死亡。—YN

摘要

基因毒性治疗如放射线作为一线癌症治疗，但导致肿瘤复发的获得性抵抗很常见。我们发现，癌细胞在照射期间通过可逆地增加全基因组DNA断裂来维持活力，从而限制过早的有丝分裂进展。我们鉴定出caspase激活的DNase（CAD）作为在特定位点造成这些新生DNA病变的核酸酶，这些位点靠近染色质修饰的CCCTC结合因子（CTCF）位点。CAD核酸酶活性通过DNA损伤反应激酶的磷酸化来调控，独立于caspase活性。反过来，CAD活性的丧失损害细胞命运决定，使癌细胞对辐射诱导的DNA双链断裂脆弱。我们的观察突出了一种癌症选择性的生存适应，即肿瘤细胞部署受调控的DNA断裂来界定治疗引发的DNA损伤的有害效应。

原文链接：

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