The circadian clock is an evolutionarily conserved time-keeping mechanism that, through the regulation of rhythmic gene expression, coordinates the physiology of an organism with daily environmental cycles. Because virtually all aspects of human physiology and behavior are linked to the clock, abnormalities in the circadian system are associated with a wide range of diseases such as sleep disorders, cardiovascular disease, metabolic syndrome, and cancer. In addition, the clock controls temporal aspects of drug metabolism and vulnerability to cytotoxic agents. Thus, knowing what genes and proteins are regulated by the clock, and the mechanisms of this regulation, are necessary to understand clock-associated diseases and rhythmic drug metabolism. The primary focus of research on circadian control of gene expression has been at the transcriptional level. However, substantial evidence exists for a role of the clock in regulating rhythmic translation. Despite this, essentialy nothing is known about how translation is controlled by the clock. In the previous funding period, using the model system Neurospora crassa, we discovered that the circadian clock controls the phosphorylation of two highly conserved central regulators of mRNA translation, eukaryotic elongation factor 2 (eEF2), and eukaryotic initiation factor 2? (eIF2?), both peaking in activity a night. In addition, we found that the clock controls the levels of S6 kinase, a key regulator of th highly conserved initiation factor eIF4B. Using high throughput RNA-seq and ribosome profiling in wild type cells, and cells that are defective in rhythmic activity of the translation factors, w will determine if the clock regulates translation of all or just some proteins. Results from these studies will allow us to determine which proteins cycle in abundance, and using molecular genetic techniques, to decipher the mechanism used by the clock to control translation elongation (Aim 1) and initiation (Aim 2). This study will fill major gaps in our knowledge regarding which proteins accumulate with a circadian rhythm and how this regulation is controlled, and thus give us a much deeper understanding of what aspects of cell physiology and metabolism are regulated by the clock.

Public Health Relevance

Circadian clock control of protein synthesis is understudied. Our investigation of clock control of translation initiation and elongation, fueled by the discover that conserved regulatory proteins required for translation are controlled by the clock, has broad implications for understanding how the clock regulates rhythmic protein production, important in rhythmic control of drug metabolism, as well as cancer, heart disease, and metabolic disease associated with shift work and genetic mutations of the clock.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM058529-14
Application #
8754138
Study Section
Special Emphasis Panel (ZRG1-CB-F (02))
Program Officer
Sesma, Michael A
Project Start
1999-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
14
Fiscal Year
2014
Total Cost
$327,370
Indirect Cost
$89,870
Name
Texas A&M University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
020271826
City
College Station
State
TX
Country
United States
Zip Code
77845
Caster, Stephen Z; Castillo, Kathrina; Sachs, Matthew S et al. (2016) Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. Proc Natl Acad Sci U S A 113:9605-10
Wu, Cheng; Yang, Fei; Smith, Kristina M et al. (2014) Genome-wide characterization of light-regulated genes in Neurospora crassa. G3 (Bethesda) 4:1731-45
Hurley, Jennifer M; Dasgupta, Arko; Emerson, Jillian M et al. (2014) Analysis of clock-regulated genes in Neurospora reveals widespread posttranscriptional control of metabolic potential. Proc Natl Acad Sci U S A 111:16995-7002
Goldsmith, Charles S; Bell-Pedersen, Deborah (2013) Diverse roles for MAPK signaling in circadian clocks. Adv Genet 84:1-39
Bennett, Lindsay D; Beremand, Phillip; Thomas, Terry L et al. (2013) Circadian activation of the mitogen-activated protein kinase MAK-1 facilitates rhythms in clock-controlled genes in Neurospora crassa. Eukaryot Cell 12:59-69
Lamb, Teresa M; Vickery, Justin; Bell-Pedersen, Deborah (2013) Regulation of gene expression in Neurospora crassa with a copper responsive promoter. G3 (Bethesda) 3:2273-80
Lamb, Teresa M; Finch, Katelyn E; Bell-Pedersen, Deborah (2012) The Neurospora crassa OS MAPK pathway-activated transcription factor ASL-1 contributes to circadian rhythms in pathway responsive clock-controlled genes. Fungal Genet Biol 49:180-8
Lamb, Teresa M; Goldsmith, Charles S; Bennett, Lindsay et al. (2011) Direct transcriptional control of a p38 MAPK pathway by the circadian clock in Neurospora crassa. PLoS One 6:e27149
Lakin-Thomas, Patricia L; Bell-Pedersen, Deborah; Brody, Stuart (2011) The genetics of circadian rhythms in Neurospora. Adv Genet 74:55-103
Bell-Pedersen, Deborah (2010) Fungal photobiology. Introduction. Fungal Genet Biol 47:879-80

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