The ability to cope with environmentalstress is essential to cellular survival, forcing organisms to develop sophisticated mechanisms by which cellular components are protected from stress-induced damage. Unfortunately,only little is known about the changes that occur in mRNA metabolism in response to stress. However, recent evidence from S. cerevisiae has shown that Heat Shock Factor (HSF) activates the expression of several genes likely to be involved in mRNA metabolism. One such gene is CTH1, encoding a tandem-zinc-finger protein whose human homologue, TTP, has been shown to promote the degradation of AU-rich element (ARE) containing mRNAs like TNF-a and c-fos. Interestingly, mammalian Tisl Ib, also a homologue of TTP is, like Cthl, inducible by stress, though it is not known if this induction is HSF dependent. Together these findings strongly suggest a role for ARE-mediated mRNA degradation in cellular stress-responses. This proposal aims to elucidate the changes that occur in mRNA metabolism during stress and the importance of these changes in cellular responses to stress. Specifically, I propose to determine the role of Cthl in mediating the degradation of ARE containing mRNAs during heat stress, explore if stress-dependent induction of Tisl Ib is HSF-dependent, and to characterize mRNAs downregulated by Tisl Ib during stress and explore their role in stress-responses. Lastly, I aim to elucidate if mammalian TTP and Tisl Ib expressed in yeast preferentially utilize the 5'-3' mRNA decay pathway during times of cell stress. These questions will be explored through the use of microarray analysis, in vivo and in vitro protein-protein and protein-RNA interaction studies, and biochemical experiments to determine the global effects of Cthl, TTP and Tisl Ib on mRNA half-life.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-G (20))
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Haynes, Susan R
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Duke University
Schools of Medicine
United States
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Neef, Daniel W; Jaeger, Alex M; Gomez-Pastor, Rocio et al. (2014) A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1. Cell Rep 9:955-66
Neef, Daniel W; Jaeger, Alex M; Thiele, Dennis J (2013) Genetic selection for constitutively trimerized human HSF1 mutants identifies a role for coiled-coil motifs in DNA binding. G3 (Bethesda) 3:1315-24
Neef, Daniel W; Jaeger, Alex M; Thiele, Dennis J (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10:930-44
Batista-Nascimento, Liliana; Neef, Daniel W; Liu, Phillip C C et al. (2011) Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast. PLoS One 6:e15976
Neef, Daniel W; Turski, Michelle L; Thiele, Dennis J (2010) Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 8:e1000291
Neef, Daniel W; Thiele, Dennis J (2009) Enhancer of decapping proteins 1 and 2 are important for translation during heat stress in Saccharomyces cerevisiae. Mol Microbiol 73:1032-42