Transcriptional pausing induced by ionizing radiation enables the acquisition of radioresistance in nasopharyngeal carcinoma.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-01-05 DOI:10.1093/jmcb/mjad044
Honglu Liu, Huanyi Fu, Chunhong Yu, Na Zhang, Canhua Huang, Lu Lv, Chunhong Hu, Fang Chen, Zhiqiang Xiao, Zhuohua Zhang, Huasong Lu, Kai Yuan
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Abstract

Lesions on the DNA template can impact transcription via distinct regulatory pathways. Ionizing radiation (IR) as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome. How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood. Here, we report an increase in the paused RNA polymerase II (RNAPII), as indicated by the phosphorylation at serine 5 residue of its C-terminal domain, in recurrent nasopharyngeal carcinoma (NPC) patient samples after IR treatment and cultured NPC cells developing IR resistance. Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b, a CDK9-CycT1 heterodimer, attenuates IR resistance of NPC cells. Interestingly, the poly(ADP-ribosyl)ation of CycT1, which disrupts its phase separation, is elevated in the IR-resistant cells. Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity. Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII. Particularly, we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistance factor, whose downregulation results in the increased chromosome instability, enabling the development of IR resistance. Overall, our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance, opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NPC.

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电离辐射诱导的转录暂停可使鼻咽癌获得放射抗性。
DNA 模板上的损伤可通过不同的调控途径影响转录。电离辐射(IR)是治疗许多恶性肿瘤的主要方法,它通过诱导基因组中的各种 DNA 损伤产生大部分细胞毒性。人们对红外治疗如何改变转录周期以及它是否会导致放射抗药性的产生仍然知之甚少。在这里,我们报告了在接受红外线治疗后的复发性鼻咽癌(NPC)患者样本中,暂停的RNA聚合酶II(RNAPII)增加的情况,其C端结构域丝氨酸5残基的磷酸化表明了这一点。通过抑制与 TFIIH 相关的 CDK7 或刺激 CDK9-CycT1 异源二聚体中的正转录延伸因子 b 来减少暂停的 RNAPII 池,可减轻鼻咽癌细胞的红外抗性。有趣的是,在耐红外细胞中,CycT1 的多(ADP-核糖基)硫酸化会破坏其相分离。突变 CycT1 的主要多聚(ADP-核糖基)连接位点可减少 RNAPII 的暂停并恢复对 IR 的敏感性。全基因组染色质免疫沉淀和测序分析表明,一些参与辐射响应和细胞周期控制的基因受到暂停的 RNAPII 的调控。特别是,我们发现受这种调控的 NIMA 相关激酶 NEK7 是一种新的放射抗性因子,它的下调会导致染色体不稳定性增加,从而产生红外抗性。总之,我们的研究结果突显了转录周期的改变与获得红外耐药性之间的新联系,为提高放疗疗效和挫败鼻咽癌的放射耐药性开辟了新的机遇。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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