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

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

Authors :
Liu, Honglu
Fu, Huanyi
Yu, Chunhong
Zhang, Na
Huang, Canhua
Lv, Lu
Hu, Chunhong
Chen, Fang
Xiao, Zhiqiang
Zhang, Zhuohua
Lu, Huasong
Yuan, Kai
Source :
Journal of Molecular Cell Biology; Jul2023, Vol. 15 Issue 7, p1-16, 16p
Publication Year :
2023

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16742788
Volume :
15
Issue :
7
Database :
Complementary Index
Journal :
Journal of Molecular Cell Biology
Publication Type :
Academic Journal
Accession number :
177375397
Full Text :
https://doi.org/10.1093/jmcb/mjad044