Molecular Bases for Circadian Clocks

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

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The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease

Getting a good night's sleep is on everyone's to-do list So is, no doubt, staying awake during late afternoon seminars Our internal clocks control these and many more workings of the body, and disruptions of the circadian clocks predispose individuals to depression, obesity and cancer Mutations in kinases and phosphatases in hamsters, flies, fungi and humans highlight how our timepieces are regulated and provide clues as to how we might be able to manipulate them

Post-translational modifications regulate the ticking of the circadian clock

Differentiation and secondary metabolism are correlated processes in fungi that respond to light. In
Aspergillus nidulans
, light inhibits sexual reproduction as well as secondary metabolism. We identified
the heterotrimeric
velvet
complex VelB/VeA/LaeA connecting light-responding developmental
regulation and control of secondary metabolism. VeA, which is primarily expressed in the dark,
physically interacts with VelB, which is expressed during sexual development. VeA bridges VelB to the
nuclear master regulator of secondary metabolism, LaeA. Deletion of either
velB
or
veA
results in
defects in both sexual fruiting-body formation and the production of secondary metabolites.

VelB/VeA/LaeA Complex CoordinatesLight Signal with Fungal Developmentand Secondary Metabolism

Correct daily phasing of transcription confers an adaptive advantage to almost all organisms, including higher plants In this study, we describe a hypothesis-driven network discovery pipeline that identifies biologically relevant patterns in genome-scale data To demonstrate its utility, we analyzed a comprehensive matrix of time courses interrogating the nuclear transcriptome of Arabidopsis thaliana plants grown under different thermocycles, photocycles, and circadian conditions We show that 89% of Arabidopsis transcripts cycle in at least one condition and that most genes have peak expression at a particular time of day, which shifts depending on the environment Thermocycles alone can drive at least half of all transcripts critical for synchronizing internal processes such as cell cycle and protein synthesis We identified at least three distinct transcription modules controlling phase-specific expression, including a new midnight specific module, PBX/TBX/SBX We validated the network discovery pipeline, as well as the midnight specific module, by demonstrating that the PBX element was sufficient to drive diurnal and circadian condition-dependent expression Moreover, we show that the three transcription modules are conserved across Arabidopsis, poplar, and rice These results confirm the complex interplay between thermocycles, photocycles, and the circadian clock on the daily transcription program, and provide a comprehensive view of the conserved genomic targets for a transcriptional network key to successful adaptation

/pdf/network-discovery-pipeline-elucidates-conserved-time-of-day-38gv4cwyo3.pdf

Network discovery pipeline elucidates conserved time-of-day-specific cis-regulatory modules.

The clock gene period-4 (prd-4) in Neurospora was identified by a single allele displaying shortened circadian period and altered temperature compensation. Positional cloning followed by functional tests show that PRD-4 is an ortholog of mammalian checkpoint kinase 2 (Chk2). Expression of prd-4 is regulated by the circadian clock and, reciprocally, PRD-4 physically interacts with the clock component FRQ, promoting its phosphorylation. DNA-damaging agents can reset the clock in a manner that depends on time of day, and this resetting is dependent on PRD-4. Thus, prd-4, the Neurospora Chk2, identifies a molecular link that feeds back conditionally from circadian output to input and the cell cycle.

https://science.sciencemag.org/content/sci/313/5787/644.full.pdf

The Neurospora checkpoint kinase 2: a regulatory link between the circadian and cell cycles.

SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells.

A highly efficient transformation system mediated by polyethylene glycol was developed for the cultivated mushroom Pleurotus ostreatus. Eighty to 180 integrative and stable-resistant colonies appeared per mug of DNA per 10(7) viable protoplasts in a transformation experiment with the hygromycin B phosphotransferase gene (hph), which is about 40-1800 times higher than that previously reported in P. ostreatus. One hundred to 150 transformants emitting green fluorescence were observed per mug of DNA per 10(7) viable protoplasts in a transformation with the green fluorescent protein gene, but green fluorescence disappeared 30 h after transformation, suggesting that the green fluorescent protein gene was only transiently expressed in P. ostreatus. Plasmid pAN7-1 was also transferred into two important cultivated mushrooms, Ganoderma lucidum and Lentinus edodes, and 120-150 and 85-100 transformants per mug of DNA per 10(7) viable protoplasts were obtained, respectively, which is seven to 38 times and 24-28 times greater than previously reported. These data indicate that this new polyethylene glycol-mediated transformation procedure is highly efficient for mushrooms, and could be a useful tool in mushroom improvement by gene engineering.

A highly efficient polyethylene glycol‐mediated transformation method for mushrooms

Hydrogen donors and acceptors and basic amino acids jointly contribute to carcinogenesis.

Acetic acid and ethanol are structurally similar to oxalate. Oxalate is produced from the shunt of Krebs cycle and other metabolic pathways. Both acetic acid and ethanol can reduce the risks of heart diseases and extend lifespan, perhaps by blocking the generation of oxalate. However, excessive intake of ethanol is associated with moderate cancer risks, which is likely to be associated with its hydrogen bonding capacity that enhances local strong acid formation and subsequent mutagenesis. Observations in China-based vinegar factories have demonstrated that few cancer cases appeared over several decades, suggesting that the weak acid can counteract strong acids such as locally formed hydrochloric acid and reduce mutagenesis and carcinogenesis. This property is superior to ethanol as acetic acid can reduce risks for either cardiovascular disease or cancer. The Krebs cycle is capable of generating both protons and short chain organic acids, and organic acids could antagonise strong acids. When the protons are in excess, cancer may occur. When organic acids are over-produced, age-related diseases then appear. Whether vinegar or acetic acid can substitute ethanol or wines in the prevention of heart diseases warrants further investigation.

Qiuyun Liu

Papers

The Neurospora checkpoint kinase 2: a regulatory link between the circadian and cell cycles.

SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells.

A highly efficient polyethylene glycol‐mediated transformation method for mushrooms

Hydrogen donors and acceptors and basic amino acids jointly contribute to carcinogenesis.

Can acetic acid substitute ethanol for the reduction of cardiovascular disease risks