The roles of RNA helicases in DNA damage repair and tumorigenesis reveal precision therapeutic strategies.
The roles of RNA helicases in DNA damage repair and tumorigenesis reveal precision therapeutic strategies.
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RNA 解旋酶在 DNA 损伤修复和肿瘤发生中的作用揭示了精准治疗策略。
DOI：
10.1158/0008-5472.can-21-2187
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发表时间：
2022-01
期刊：
影响因子：
11.2
通讯作者：
Tan Rong
中科院分区：
文献类型：
--
作者：
Xie Jinru;Wen Ming;Zhang Jiao;Wang Zheng;Wang Meng;Qiu Yanfang;Zhao Wenchao;Zhu Fang;Yao Mianfeng;Rong Zhuoxian;Hu Wenfeng;Pei Qian;Sun Xiaoxiang;Li Jinchen;Mao Zhiyong;Sun Lun-Quan;Tan Rong
DEAD-box RNA解旋酶属于一大类RNA加工因子，在解开RNA螺旋和核糖体RNA生物发生中起着至关重要的作用。新出现的证据表明，RNA解旋酶与基因组稳定性有关，但这种联系背后的机制仍然知之甚少。在这项研究中，我们使用多平台蛋白质基因组数据库对RNA解旋酶进行了全面的分析。超过50%(28/49)的RNA解旋酶在多种肿瘤组织中高表达，超过60%(17/28)的肿瘤相关成员直接参与DNA损伤修复(DDR)。修复动力学分析表明，这些RNA解旋酶参与了广泛的DDR途径。这些因素中有DDX21，它在结直肠癌中显著上调。DDX21基因的高表达导致染色体交换频繁，基因组片段化增加。在机制上，DDX21的异常高表达通过延迟同源重组修复和增加复制压力而触发不适当的修复过程，导致基因组不稳定和肿瘤的发生。不同的化疗药物对DDX21诱导的基因组脆性肿瘤细胞具有更高的杀伤力，为DDX21高表达肿瘤的治疗提供了一个前景。本研究揭示了RNA解旋酶在DNA损伤中的作用及其与癌症的关系，这将为高表达RNA解旋酶的癌症患者拓展治疗策略，提高精确度。
DEAD-box RNA helicases belong to a large group of RNA processing factors and play vital roles unwinding RNA helices and in ribosomal RNA biogenesis. Emerging evidence indicates that RNA helicases are associated with genome stability, yet the mechanisms behind this association remain poorly understood. In this study, we performed a comprehensive analysis of RNA helicases using multiplatform proteogenomic databases. Over 50% (28/49) of detected RNA helicases were highly expressed in multiple tumor tissues, and more than 60% (17/28) of tumor-associated members were directly involved in DNA damage repair (DDR). Analysis of repair dynamics revealed that these RNA helicases are engaged in an extensively broad range of DDR pathways. Among these factors is DDX21, which was prominently upregulated in colorectal cancer. The high expression of DDX21 gave rise to frequent chromosome exchange and increased genome fragmentation. Mechanistically, aberrantly high expression of DDX21 triggered inappropriate repair processes by delaying homologous recombination repair and increasing replication stress, leading to genome instability and tumorigenesis. Treatment with distinct chemotherapeutic drugs caused higher lethality to cancer cells with genome fragility induced by DDX21, providing a perspective for treatment of tumors with high DDX21 expression. This study revealed the role of RNA helicases in DNA damage and their associations with cancer, which could expand therapeutic strategies and improve precision treatments for cancer patients with high expression of RNA helicases.