分子细胞生物学前沿-博士-PPT文档.ppt
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1、Main Points Transcription process of eukaryotic gene. P-TEFb: functions and its Activity regulation I. Transcription process Steps of class II gene transcription Promotor clearence Initiation PIC assembly Termination Elongation TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH RNA polymerase II (Pol II)
2、The class II pre-initiation complex (PIC) RNA polymerase II (Pol II) 12 subunites: Rpb1- Rpb12 About 500Kda of MW Rpb1: largest subunit, CTD: Y1S2P3T4S5P6S7 Yest: 26 repeats C. elegans: 32 repeats Drosophila 42 repeats Mammals: 52 repeats Pre-initiation Pol II CTD PIC assembly IIF IIH IIE PIC Pol II
3、 CTD IIF Pol II CTD IIF II D II AIIB IIH IIE +1 DNA temp TATA PIC Pol II CTD II D II A IIB IIF IIH IIE Initiation 5 5 5 5 5 Pol II 5 5 5 5 5 +1 DNA temp TATA Promoter clearance 20-30 nt Pol II CTD 5 55 5 5 DNA temp TATA II S DSIFNELF MT Pausing Capping Pol II CTD 5 55 5 5 DNA temp TATA II S RNA DSIF
4、NELF Early elongation 5-triphosphatase guanyltransferase N C N C methyltransferase MT MT N C N C Capping Early elongation DNA temp Productive Elongation CycT1 CDK9 P-TEFb RNA CycT1 CDK9 P-TEFb Pol II CTD 5 55 5 5 II S DSIF 2 2 2 2 CycT1 CDK9 P-TEFb NELF Pol II CTD 5 55 5 5 II S DSIF Capped short mRN
5、A 2 2 2 2 P P CycT1 CDK9 P-TEFb Splicing 5 55 5 5 Pol II 2 2 2 2 2 RNA DNA temp RNA U snRNP Productive Elongation Splicing CycT1 CDK9 P-TEFb FCP1 Pol II Pol II CTD 2 5 5 5 5 2 2 2 Pol II 2 5 5 5 5 2 2 2 +1 5 5 5 5 Pol II 5 cap RNA 5 5 5 5 2 2 2 2 Pol II CTD TFIIH NFkB Sp1 NFAT Pol II Steps: Pre-init
6、iation Initiation Promoter clearance Elongation Termination Initiation Early elongation Promoter clearance Elongation TerminationPre-initiation Transcription cycle Transcription Process P-TEFb, its functions and activity regulation P-TEFb: composition and property Discovered in 1995. (positive trans
7、cription elongation factor b) A heterodimer of Cdk9 and cyclin T, including T1, T2a, T2b and Cyclin K. But 80% P-TEFb is CDK9/Cyclin T1. kinase, phosphorylates CTD of Pol II, DSIF and NELF. CycT1 Cdk9 Physiological functions A global transcriptional elongation factor Essential for more than 80% mRNA
8、 transcription Essential for embryo development CTD Pol II RNA NELF Nuc 失败转录 CycT1 Cdk9 P-TEFb 成功转录 RNA P P P P P P P P CycT1 Cdk9 Adapted after Price, MCB 20:2629 (2000) P-TEFb在基因转录过程中的作用机制模式图 B. Pathological functions Exquisitely required for HIV-1 gene expression Abnormally high P-TEFb activity d
9、irect link to cardiac hypertrophy May also relate to tumor progression TAR RNA CTD Pol II 5 5 5 5 CTD Pol II 5 5 5 5 Abortive Transcription CTD Pol II 5 5 5 5 Short RNA CycT1 CDK9 Tat CycT1 CDK9 Tat HIV LTR +1 Tat Tat CycT1 CDK9 Tat CycT1 CDK9 Tat CycT1 CDK9 Tat 2 2 2 2 HIV P-TEFb is essential for H
10、IV-1 replication and gene expression Tat, a HIV-1 encoded protein. Trans-cyclin T1 gene causes cardiac hypertrophy Trans-vector Trans-cyclin T1 CycT1 Cdk9 7SK snRNA Inactive P-TEFb-7SK snRNP HEXIM1 HEXIM2 LARP7 MePCE HEXIM1 LARP7 Methyl donor CycT1 CDK9 HEXIM1 CycT1 CDK9 HEXIM1 MePCE MePCELARP7 CycT
11、1 CDK9 HEXIM1 MePCE 7SK LARP7 5-Cap 3-tail MePCE 3-tail capped 7SK 7SK 5-Cap 3-tail Trinity compled 7SK snRNP 3-tail Nascent 7SK 5-termini 5-Cap CycT1 CDK9 HEXIM1 7SK snRNP assemble Active P-TEFb for general transcription CycT1 Cdk9 Brd4 P P P P P P P P CycT1 Cdk9 Brd4 CTD Pol II mRNA mRNA Pol II Cy
12、cT1 Cdk9 HEXIM1 7SK RNA CycT1 Cdk9 Brd4 Stress/hypertrophic signals/estrogen/ HIV infection inactive P-TEFb CycT1 Cdk9 Brd4 active P-TEFb Recruitment of P-TEFb for stimulation of transcriptional elongation by bromodomain protein Brd4 (Submitted to: Mol Cell) CycT1 Cdk9Brd4 CycT1 Cdk9 HEXIM1 7SK snRN
13、A Inactive P-TEFbActive P-TEFb CycT1 Cdk9 P P P 3/4 1/4 ? How is 7SK snRNP disrupted? CycT1 Cdk9HEXIM1 7SK snRNA Inactive P-TEFb P P P P P P P P P P P P P P P P Phosphorylated P-TEFb is tagged for inhibition through association with 7SK snRNA PP1 treatment Or Stress: Act D, DRB, UV Dephosphorylation
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