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 ...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.展开更多
10,11-Dehydrocurvularin(DCV)is a natural-product macrolide that has been shown to exert anti-inflammatory activity.However,the underlying mechanism of its anti-inflammatory activity remains poorly understood.Aberrant ...10,11-Dehydrocurvularin(DCV)is a natural-product macrolide that has been shown to exert anti-inflammatory activity.However,the underlying mechanism of its anti-inflammatory activity remains poorly understood.Aberrant activation of the NLRP3 inflammasome is involved in diverse inflammation-related diseases,which should be controlled.The results showed that DCV specifically inhibited the activation of the NLRP3 inflammasome in association with reduced IL-1βsecretion and caspase-1 activation,without effect on the NLRC4 and AIM2 inflammasomes.Furthermore,DCV disturbed the interaction between NEK7 and NLRP3,resulting in the inhibition of NLRP3 inflammasome activation.The C=C double bond of DCV was required for the NLRP3 inflammasome inhibition induced by DCV.Importantly,DCV ameliorated inflammation in vivo through inhibiting the NLRP3 inflammasome.Taken together,our study reveals a novel mechanism by which DCV suppresses inflammation,which indicates the potential role of DCV in NLRP3 inflammasome-driven inflammatory disorders.展开更多
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)+2 种基金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.
文摘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.
基金the National Natural Science Foundation of China(No.81902852)China Postdoctoral Science Foundation(No.2020M670220)+2 种基金the Natural Science Foundation of Hubei Province of China(No.2022CFB481)the Natural Science Foundation of Hubei Provincial Department of Education(No.T2022021)Wudang Local Chinese Medicine Research of Hubei University of Medicine(No.WDCM2020004).
文摘10,11-Dehydrocurvularin(DCV)is a natural-product macrolide that has been shown to exert anti-inflammatory activity.However,the underlying mechanism of its anti-inflammatory activity remains poorly understood.Aberrant activation of the NLRP3 inflammasome is involved in diverse inflammation-related diseases,which should be controlled.The results showed that DCV specifically inhibited the activation of the NLRP3 inflammasome in association with reduced IL-1βsecretion and caspase-1 activation,without effect on the NLRC4 and AIM2 inflammasomes.Furthermore,DCV disturbed the interaction between NEK7 and NLRP3,resulting in the inhibition of NLRP3 inflammasome activation.The C=C double bond of DCV was required for the NLRP3 inflammasome inhibition induced by DCV.Importantly,DCV ameliorated inflammation in vivo through inhibiting the NLRP3 inflammasome.Taken together,our study reveals a novel mechanism by which DCV suppresses inflammation,which indicates the potential role of DCV in NLRP3 inflammasome-driven inflammatory disorders.
