Most eukaryotic messenger RNA precursors (pre-mRNAs) must undergo extensive co- transcriptional processing in the nucleus before they can be exported to the cytoplasm and function as mRNAs. The processing events include 5??-end capping, splicing, and 3??- end cleavage and polyadenylation. The 3'-end processing of most pre-mRNAs requires a large number of protein factors for its execution, including cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factors I and II, and poly(A) polymerase (PAP). The 3'-end processing machinery in yeast has similarity to that in mammals, although there are also significant differences. Replication-dependent histone pre-mRNAs contain a conserved stem-loop near their 3??- end and employ a distinct machinery for its processing, although it shares some protein factors with the canonical pre-mRNA 3??-end processing machinery. mRNA 5??-end capping occurs early during transcription by RNA polymerase II, and it was generally believed that capping always proceeds to completion. We have recently discovered that the Rai1/DXO family of proteins are part of a mRNA capping quality surveillance mechanism. They can possess RNA 5??-end pyrophosphohydrolase (PPH) and decapping activities, and help remove incompletely capped mRNAs from cells. Despite the extensive studies on these mRNA processing and quality control factors, significant gaps remain in our knowledge of their molecular mechanisms of action. We will carry out structural studies on the protein factors and their complexes, and assess the structural observations by careful biochemical and functional experiments. The proposed project will greatly enhance our understanding of these important events in mRNA lifecycle.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Graduate Schools
New York
United States
Zip Code
Sun, Yadong; Zhang, Yixiao; Hamilton, Keith et al. (2018) Molecular basis for the recognition of the human AAUAAA polyadenylation signal. Proc Natl Acad Sci U S A 115:E1419-E1428
Yun, Ji-Sook; Yoon, Je-Hyun; Choi, Young Jun et al. (2018) Molecular mechanism for the inhibition of DXO by adenosine 3',5'-bisphosphate. Biochem Biophys Res Commun 504:89-95
Luo, Shukun; Tong, Liang (2018) Structural biology of the separase-securin complex with crucial roles in chromosome segregation. Curr Opin Struct Biol 49:114-122
Zhang, Yinglu; Shan, Chun-Min; Wang, Jiyong et al. (2017) Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. Sci Rep 7:43906
Zhu, Yiping; Luo, Shukun; Sabo, Yosef et al. (2017) Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling. Cell Host Microbe 21:220-230
Jiao, Xinfu; Doamekpor, Selom K; Bird, Jeremy G et al. (2017) 5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding. Cell 168:1015-1027.e10
Luo, Shukun; Tong, Liang (2017) Molecular mechanism for the regulation of yeast separase by securin. Nature 542:255-259
Wu, Yixuan; Albrecht, Todd R; Baillat, David et al. (2017) Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance. Proc Natl Acad Sci U S A 114:4394-4399
Aik, Wei Shen; Lin, Min-Han; Tan, Dazhi et al. (2017) The N-terminal domains of FLASH and Lsm11 form a 2:1 heterotrimer for histone pre-mRNA 3'-end processing. PLoS One 12:e0186034
Liu, Zheng; Gutierrez-Vargas, Cristina; Wei, Jia et al. (2017) Determination of the ribosome structure to a resolution of 2.5 Å by single-particle cryo-EM. Protein Sci 26:82-92

Showing the most recent 10 out of 14 publications