Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage
Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage
复制标题
DOI：
10.1083/jcb.202002175
复制
发表时间：
2020-08-03
影响因子：
7.8
通讯作者：
Penengo, Lorenza
中科院分区：
文献类型：
--
作者：
Raso, Maria Chiara;Djoric, Nikola;Penengo, Lorenza
DNA复制受泛素系统的高度调节，泛素系统在应激中起关键作用。泛素样修饰物ISG15（干扰素刺激基因15）由干扰素、细菌和病毒感染以及DNA损伤诱导，但它也在许多类型的癌症中组成性表达，尽管它在肿瘤发生中的作用在很大程度上仍然难以捉摸。在这里，我们发现ISG15定位于复制叉，与PCNA和新生DNA复合，在那里它调节DNA合成。事实上，高水平的ISG 15（内在的或由干扰素β诱导的）会加速DNA复制叉进程，导致广泛的DNA损伤和染色体畸变。这种效应在很大程度上不依赖于15G15缀合，并且依赖于ISG15与DNA解旋酶RECQ1的功能性相互作用，其促进停滞的复制叉的重新启动。此外，升高的ISG15水平使细胞对癌症化疗治疗敏感。我们认为ISG15上调使细胞暴露于复制应激，影响基因组稳定性和对遗传毒性药物的反应。
DNA replication is highly regulated by the ubiquitin system, which plays key roles upon stress. The ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) is induced by interferons, bacterial and viral infection, and DNA damage, but it is also constitutively expressed in many types of cancer, although its role in tumorigenesis is still largely elusive. Here, we show that ISG15 localizes at the replication forks, in complex with PCNA and the nascent DNA, where it regulates DNA synthesis. Indeed, high levels of ISG15, intrinsic or induced by interferon-beta, accelerate DNA replication fork progression, resulting in extensive DNA damage and chromosomal aberrations. This effect is largely independent of 15G15 conjugation and relies on ISG15 functional interaction with the DNA helicase RECQ1, which promotes restart of stalled replication forks. Additionally, elevated ISG15 levels sensitize cells to cancer chemotherapeutic treatments. We propose that ISG15 up-regulation exposes cells to replication stress, impacting genome stability and response to genotoxic drugs.