核糖核酸酶 ZC3H12A 是小细胞肺癌细胞 DNA 损伤后自残 DNA 断裂的必要条件

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2024-03-18 DOI:10.1007/s13402-024-00941-x
Mingjun Lu, Qing Gao, Renjing Jin, Meng Gu, Ziyu Wang, Xiaobo Li, Weiying Li, Jinghui Wang, Teng Ma
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引用次数: 0

摘要

放疗是治疗小细胞肺癌(SCLC)的一线疗法;然而,放射抗药性伴随着放疗,阻碍了小细胞肺癌患者的预后。其潜在的机制仍然难以捉摸。在这里,我们发现在辐射后,SCLC 细胞中存在自我损伤的 DNA 断裂。此外,通过核酸酶 siRNA 筛选结合高含量 ArrayScan™ 细胞分析仪,我们发现核糖核酸酶 ZC3H12A 是辐射后自残 DNA 断裂和 SCLC 细胞在 DNA 损伤后存活的必要条件。ZC3H12A 的表达在 DNA 损伤时增加,当 ZC3H12A 被敲除时,细胞的 DNA 修复能力受损,表现为 DNA 损伤修复蛋白 BRCA1 的表达减少,DNA 损伤位点的 γH2AX 增加。集落形成试验表明,ZC3H12A 基因敲除可使小细胞肺癌放疗增敏。因此,核糖核酸酶 ZC3H12A 可调节小细胞肺癌的内源性二次断裂并影响 DNA 损伤修复。ZC3H12A可能是小细胞肺癌放疗的一个重要靶点。
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The Ribonuclease ZC3H12A is required for self-inflicted DNA breaks after DNA damage in small cell lung cancer cells

Radiotherapy is the first line treatment for small cell lung cancer (SCLC); However, radio-resistance accompanies with the treatment and hampers the prognosis for SCLC patients. The underlying mechanisms remains elusive. Here we discovered that self-inflicted DNA breaks exist in SCLC cells after radiation. Moreover, using nuclease siRNA screening combined with high-content ArrayScan™ cell analyzer, we identified that Ribonuclease ZC3H12A is required for the self-inflicted DNA breaks after radiation and for SCLC cell survival after DNA damage. ZC3H12A expression was increased in response to DNA damage and when ZC3H12A was knocked down, the DNA repair ability of the cells was impaired, as evidenced by decreased expression of the DNA damage repair protein BRCA1, and increased γH2AX at DNA damage sites. Colony formation assay demonstrates that ZC3H12A knocked down sensitized small cell lung cancer radiotherapy. Therefore, the Ribonuclease ZC3H12A regulates endogenous secondary breaks in small cell lung cancer and affects DNA damage repair. ZC3H12A may act as an important radiotherapy target in small cell lung cancer.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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