WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest. Moreover, we present new evidence that WRN depletion results in early changes of RNA polymerase III and RNase P activities, thereby implicating chromatin-associated tRNA enzymes in WRN-related stress response. Combined with the recently discovered roles of RecQ helicases in cancer, current data support the targeting prospect of these genome guardians, as a means of developing clinical phases aimed at diminishing adaptive resistance to present targeted therapies.

中文翻译：

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靶向抑制WRN解旋酶，复制应激和癌症。

WRN解旋酶在基因组维护中具有多个作用，例如复制，碱基切除修复，重组，DNA损伤反应和转录。通常在人类癌症中发现这些过程上调，其中许多表现出WRN水平升高。因此，这种RecQ解旋酶的直接抑制可能对选择性癌症治疗有益。通过使用小分子抑制剂或应用RNA干扰和EGS / RNase P靶向系统，抑制WRN是可行的。明显地，由于有丝分裂灾难，解旋酶的消耗导致细胞活力的严重降低，这是由DNA修复失败和叉进行停滞引起的复制压力触发的。此外，我们提供了新证据，表明WRN耗竭会导致RNA聚合酶III和RNase P活性的早期变化，从而将染色质相关的tRNA酶牵涉到WRN相关的应激反应中。结合最近发现的RecQ解旋酶在癌症中的作用，当前数据支持这些基因组监护人的靶向前景，作为发展临床阶段的一种手段，旨在减少对现有靶向疗法的适应性抵抗力。