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

作　　者：Honglu Liu Huanyi Fu Chunhong Yu Na Zhang Canhua Huang Lu Lv Chunhong Hu Fang Chen Zhiqiang Xiao Zhuohua Zhang Huasong Lu Kai Yuan 

机构地区：[1]Hunan Key Laboratory of Molecular Precision Medicine,Department of Oncology,Xiangya Hospital,Central South University,Changsha 410008,China [2]Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology,Life Sciences Institute,Zhejiang University,Hangzhou 310058,China [3]Hunan Key Laboratory of Medical Genetics,School of Life Sciences,Central South University,Changsha 410008,China [4]Department of Oncology,The Second Xiangya Hospital,Central South University,Changsha 410011,China [5]Research Center of Carcinogenesis and Targeted Therapy,Xiangya Hospital,Central South University,Changsha 410008,China [6]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008,China [7]The Biobank of Xiangya Hospital,Central South University,Changsha 410008,China

出　　处：《Journal of Molecular Cell Biology》2023年第7期15-30,共16页分子细胞生物学报（英文版）

基　　金：This project has been supported by grants from the National Natural ScienceFoundation of China(32170821 and 92153301 to K.Y.and 32101034 to F.C.);the Ministry of Science and Technologyyof the People's Republic of China(2021YFC2701202);Department of Science&Technology of Hunan Province(2021J10054 and 2019SK1012 to K.Y.,2021J41049 to C.Y.,and the Innovative Team Program 2019RS1010);Central South University(the Innovationdriven Team Project 2020CX016);K.Y.is supported by the National Thousand Talents Program for Young Outstanding Scientists.

摘　　要：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 radioresistancefactor,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.

关 键 词：RNA polymerase II transcriptional pausing RADIORESISTANCE CDK7 NEK7 nasopharyngeal carcinoma 

分 类 号：R739.63[医药卫生—肿瘤]