Precise regulation of transcription termination is essential to cellular growth and survival. While premature stopping of transcription may produce truncated and defective transcripts;stopping too late may disrupt the regulation of downstream genes in the same orientation and generate antisense RNA against genes in the opposite orientation. Either outcome would have significant impact on gene expression. Thus, it is not surprising that transcription termination defects are causally associated with various human diseases, such as thrombophilia, thalassemia and cancer. We have previously demonstrated in a recent study that the mRNA cap-binding protein complex functions in conjunction with antitermination factor Npl3p to regulate transcription termination. In this project, I will continue to shed light on the mechanisms of eukaryotic transcription termination in the model organism of budding yeast using a combination of genetic and molecular biological methods. My study will focus on the regulation of eukaryotic transcription termination through Npl3p and the functional coupling of eukaryotic transcription termination with RNA surveillance. For the first part, I will define the influence of post-translational modification of Npl3p on its antitermination activity. For the second part, I will explore how cellular machineries of transcription termination and RNA surveillance are functionally coupled with each other. Particularly, I will investigate cotranscriptional recruitment of nuclear exosome Rrp6p. Because of the fundamental importance of transcription termination and high degree of conservation of transcription termination machineries from yeast to human, our findings will have important implications in human diseases caused by transcription termination defects.
Transcription termination is critical for gene expression, as defects in this process can produce mRNA transcripts that are unstable or encode defective proteins, and can also interfere with proper expression of neighboring genes. Accordingly, such defects are associated with some human diseases, such as thrombophilia, thalassemia and cancer. In addition, transcription termination is an important means for gene regulation in viruses including HIV. It is crucial, therefore, to develop a complete understanding of the mechanism and regulation of transcription termination. This project aims to derive new insight into the regulation of transcription termination and its link in mRNA surveillance using budding yeast as a model. Because the cellular machineries for transcription termination are highly conserved from yeast to human, our findings will have important implications in human biology and medicine.
|Kong, Ka-Yiu Edwin; Tang, Hei-Man Vincent; Pan, Kewu et al. (2014) Cotranscriptional recruitment of yeast TRAMP complex to intronic sequences promotes optimal pre-mRNA splicing. Nucleic Acids Res 42:643-60|