Regulation Of The Alternative Splicing And Function Of Cyclin T1 By The Serine-arginine-rich Protein ASF/SF2

Transcription is an indispensible step of protein metabolism in cells.The regulation of transcription determines the fate of cell proliferation and differentiation.The processing of RNA transcription is generally divided into 3 steps:initiation,elongation and termination.Numerous transcription factors were identified since 1970s and the significance of transcription initiation was well recognized during the past 40 years.However,it's until a decade ago that people are realizing the importance of transcription elongation.The majority of eukaryotic genes are transcribed by RNA polymerase ?(Pol ?)and most of these genes will be stucked at 20-60bp downstream of transcription start site untill Pol ? is further activated.This event is called transcription pause.Positive transcription elongation factor-b(P-TEFb)is required for the release of Pol ? from its pause near the gene promoters,to efficiently proceed to the transcription elongation.It consists of two core subunits-CDK9 and one of T-typed or K-typed cyclin,of which,cyclin T1/CDK9 is the major and most studied combination.We have previously identified a novel splice variant of cyclin T1,cyclin T1b,which negatively regulates the transcription elongation of HIV-1 genes as well as several host genes.In this study,we revealed the serine-arginine-rich splicing factor 1(ASF/SF2),as a regulatory factor of the alternative splicing of cyclin T1 gene.ASF/SF2 promotes the production of cyclin T1b versus cyclin Tla and regulates the expression of cyclin T1-depedent genes at the transcription level.We further found that a cis-element on exon 8 is responsible for the skipping of exon 7 mediated by ASF/SF2.Collectively,ASF/SF2 is identified as a splicing regulator of cyclin T1,which contributes to the control of the subsequent transcription events.