Replication stress and cancer: it takes two to tango.
Replication stress and cancer: it takes two to tango.
复制标题
复制应力和癌症：探戈需要两个。
DOI：
10.1016/j.yexcr.2014.09.019
复制
发表时间：
2014-11-15
影响因子：
3.7
通讯作者：
Fernández-Capetillo O
中科院分区：
文献类型：
--
作者：
Lecona E;Fernández-Capetillo O
在DNA复制过程中出现的问题需要ATR-CHK 1途径的激活，以确保叉的稳定和修复，并防止未复制的基因组进入有丝分裂。虽然该途径在细胞水平上是必不可少的，但限制其活性对某些癌细胞特别有害。在这里，我们审查复制应激（RS）和癌症之间的联系，这提供了一个使用ATR和Chk 1抑制剂在化疗的理由。首先，我们描述了癌基因诱导的RS的激活如何促进基因组重排和染色体不稳定性，这两者都可能潜在地助长致癌作用。接下来，我们回顾了有助于抑制RS的各种途径，以及这些成分中的突变如何导致癌症发病率增加和/或加速衰老。最后，我们总结的证据表明，高水平的RS肿瘤依赖于一个熟练的RS反应，因此容易受到ATR或Chk 1抑制剂。
Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.