The RNA exosome plays important roles in 3' end processing of a variety of ncRNAs and is also responsible for 3' to 5' degradation of both mRNAs and nc RNAs. By preferentially degrading aberrant mRNAs and ncRNAs it also maintains the overall fidelity of gene expression. Given the central role of the RNA exosome in a wide variety of RNA processing and degradation reactions, it is not surprising that it is required for cell viability. The long tern goal of our research is to achieve a greater understanding of how the RNA exosome carries out its diverse functions. The RNA exosome is a 10-subunit complex that adopts an overall donut-shaped structure. Nine of the subunits are catalytically inactive, and form the majority of the donut. The 10th subunit is associated with one opening of the donut and confers both 3' to 5' exoribonuclease and endoribonuclease activity on the RNA exosome complex. In the past 10 years much progress has been made in understanding the structure and biochemistry of the RNA exosome. Although isolated Rrp44 or the RNA exosome has nuclease activity in vitro, activity in vivo strictly requires over a dozen other proteins. Although it is clear that these RNA exosome cofactors control the activity and specificity of the RNA exosome, how these cofactors achieve this is essentially completely unknown. The overall goal of the proposed research is to resolve how the RNA exosome cofactors mediate its in vivo activities. We will focus on Ski7 and Rrp6, two of the three RNA exosome cofactors that are known to directly interact with the RNA exosome. Both genetic and biochemical data suggest that they are important in part because they mediate interaction with additional RNA exosome cofactors.

Public Health Relevance

The RNA exosome is a key enzyme that is required for different aspects of gene expression, including the maturation of RNA into its functional mature form and the degradation of misprocessed RNAs. Mutations that result in RNA exosome defects cause four very different human diseases. The control and specificity of this enzyme is the topic of the proposed research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Bender, Michael T
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University of Texas Health Science Center Houston
Schools of Medicine
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Marshall, Alexandra N; Han, Jaeil; Kim, Minseon et al. (2018) Conservation of mRNA quality control factor Ski7 and its diversification through changes in alternative splicing and gene duplication. Proc Natl Acad Sci U S A 115:E6808-E6816
Gao, Peng; Pinkston, Kenneth L; Bourgogne, Agathe et al. (2017) Functional studies of E. faecalis RNase J2 and its role in virulence and fitness. PLoS One 12:e0175212
Fasken, Milo B; Losh, Jillian S; Leung, Sara W et al. (2017) Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast. Genetics 205:221-237
Han, Jaeil; van Hoof, Ambro (2016) The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions. Cell Rep 16:3348-3358
Losh, Jillian S; van Hoof, Ambro (2015) Gateway Arch to the RNA Exosome. Cell 162:940-1
Losh, Jillian S; King, Alejandra Klauer; Bakelar, Jeremy et al. (2015) Interaction between the RNA-dependent ATPase and poly(A) polymerase subunits of the TRAMP complex is mediated by short peptides and important for snoRNA processing. Nucleic Acids Res 43:1848-58
Taylor, Lacy L; Jackson, Ryan N; Rexhepaj, Megi et al. (2014) The Mtr4 ratchet helix and arch domain both function to promote RNA unwinding. Nucleic Acids Res 42:13861-72
DebRoy, Sruti; Gebbie, Margo; Ramesh, Arati et al. (2014) Riboswitches. A riboswitch-containing sRNA controls gene expression by sequestration of a response regulator. Science 345:937-40
Tsanova, Borislava; Spatrick, Phyllis; Jacobson, Allan et al. (2014) The RNA exosome affects iron response and sensitivity to oxidative stress. RNA 20:1057-67
Marshall, Alexandra N; Montealegre, Maria Camila; Jiménez-López, Claudia et al. (2013) Alternative splicing and subfunctionalization generates functional diversity in fungal proteomes. PLoS Genet 9:e1003376

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