Pseudo-response regulator

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Pseudo-response regulator (PRR) refers to a group of genes that are important in the plant circadian oscillator. There are four primary PRR proteins (PRR9, PRR7, PRR5 and TOC1/PRR1) that perform the majority of interactions with other proteins within the circadian oscillator, and another (PRR3) that has limited function. These genes are all paralogs of each other, and all repress the transcription of Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY) at various times throughout the day. The expression of PRR9, PRR7, PRR5 and TOC1/PRR1 peak around morning, mid-day, afternoon and evening, respectively. As a group, these genes are one part of the three-part repressilator system that governs the biological clock in plants.

Contents

Discovery

Multiple labs identified the PRR genes as parts of the circadian clock in the 1990s. In 2000, Akinori Matsushika, Seiya Makino, Masaya Kojima, and Takeshi Mizuno were the first to understand PRR genes as pseudo-response repressor genes rather than as response regulator (ARR) genes. [1] [2] The factor that distinguishes PRR from ARR genes is the lack of a phospho-accepting aspartate site that characterizes ARR proteins. Though their research that discovered PRR genes was primarily hailed during the early 2000s as informing the scientific community about the function of TOC1 (named APRR1 by the Mizuno lab), an additional pseudo-response regulator in the Arabidopsis thaliana biological clock, [3] the information about PRR genes that Matsushika and his team found deepened scientific understanding of circadian clocks in plants and led other researchers to hypothesize about the purpose of the PRR genes. [1] Though current research has identified TOC1, PRR3, PRR5, PRR7, and PRR9 as of importance to the A. thaliana circadian clock mechanism, Matsushika et al. first categorized PRR genes into two subgroups (APRR1 and APRR2, the A stands for Arabidopsis) due to two differing amino acid structures. [4] The negative feedback loops including PRR genes, proposed by Mizuno, were incorporated into a complex repressilator circuit by Andrew Millar’s lab in 2012. [5] The conception of the plant biological clock as made up of interacting negative feedback loops is unique in comparison to mammal and fungal circadian clocks which contain autoregulatory negative feedback loops with positive and negative elements [6] (see "Transcriptional and non-transcriptional control on the Circadian clock page).

Function and Interactions

PRR3, PRR5, PRR7 and PRR9 participate in the repressilator of a negative autoregulatory feedback loop that synchronizes to environmental inputs. The repressilator has a morning, evening, and night loop that are regulated in part by the pseudo-response regulator proteins' interactions with CCA1 and LHY. CCA1 and LHY exhibit peak binding to PRR9, PRR7, and PRR5 in the morning, evening, and night, respectively. [7]

PRR3 and PRR5

When phosphorylated by an unknown kinase, PRR5 and PRR3 proteins demonstrate increased binding to TIMING OF CAB2 EXPRESSION 1 ( TOC1). This interaction stabilizes both TOC1 and PRR5 and prevents their degradation by the F-box protein ZEITLUPE (ZTL). [7] Through this mechanism, PRR5 is indirectly activated by light, as ZTL is inhibited by light. Additionally, PRR5 contributes to the transcriptional repression of the genes encoding the single MYB transcription factors CCA1 and LHY. [7]

PRR7 and PRR9

Two single MYB transcription factors, CCA1 and LHY, activate expression of PRR7 and PRR9. In turn, PRR7 and PRR9 repress CCA1 and LHY through the binding of their promoters. This interaction forms the morning loop of the repressilator of the biological clock in A. thaliana. [7] Chromatin immunoprecipitation demonstrates that LUX binds to the PRR9 promoter to repress it. Additionally, ELF3 has been shown to activate PRR9 and repress CCA1 and LHY. [7] PRR9 is also activated by alternative RNA splicing. When PRMT5 (a methylation factor) is prevented from methylating intron 2 of PRR9, a frameshift resulting in premature truncation occurs. [7]

PRR7 and PRR9 also play a role in the entrainment of A. thaliana to a temperature cycle. Double-mutant plants with inactivated PRR7 and PRR9 exhibit extreme period lengthening at high temperatures but show no change in period at low temperatures. However, the inactivation of CCA1 and LHY in the PRR7/PRR9 loss-of-function mutants shows no change in period at high temperatures—this suggests that PRR7 and PRR9 are acting by overcompensation. [7]

Interactions Within Arabidopsis

In A. thaliana, the main feedback loop is proposed to involve a transcriptional regulation between several proteins. The three main components of this loop are TOC1 (also known as PRR1), CCA1 and LHY. [8] Each individual component peaks in transcriptions at different times of day. [9] PRR 9, 7 and 5 each significantly reduce the transcription levels of CCA1 and LHY. [9] In the opposite manner, PRR 9 and 7 slightly increase the transcription levels of TOC1. [9] The Constans (CO) is also indirectly regulated by the PRR proteins as well by setting up the molecular mechanism to dictate the photosensitive period in the afternoon. [10] PRRs are also known to stabilize CO at certain times of day to mediate its accumulation. [11] This results in the regulation of early flowering in shorter photoperiods, making light sensitivity and control of flowering time important functions of the PRR class. [10]

Homologs

Paralogs

PPR3, PRR5, PRR7, and PRR9 are all paralogs of each other. They have similar structure, and all repress the transcription of CCA1 and LHY. Additionally, they are all characterized by their lack of a phospho-accepting aspartate site. These genes are also paralogs to TOC1, which is alternatively called PRR1. [7]

Orthologs

Several pseudo-response regulators have been found in Selaginella, but their function has not yet been explored. [12]

Mutants

As PRR is a family of genes, several rounds mutant screening have been performed to identify each possible phenotype.

Rhythmicity Phenotype

In regards to rhythmicity of the clock in a free running setting PRR9 and PRR5 are associated with longer and shorter periods respectively. [9] For each gene, the double mutant with PRR7 exacerbates observed trends in rhythmicity. [9] The triple mutant renders the plant arrhythmic. [9]

Flowering Time Phenotype

In terms of flowering time in long day conditions, all mutants made the observed flowering late, with PRR7 significantly more late in comparison to the other mutants. [9] All double mutants with PRR7 saw much later flowering time than the PRR5/PRR9 mutant. [9]

Light Sensitivity Phenotype

With regard to light sensitivity, particularly in red light which is associated with hypocotyl lengthening, all PRR mutants were observed to be hypo-sensitive with PRR9 showing to be less sensitive. [9] All the double mutants were equal in hyposensitivity as the PRR5 or PRR7 mutants; the triple mutant is extremely hypo-sensitive. [9]

Future research

Recent research has showed that expression of clock genes show tissue-specificity. [13] Learning about how, when, and why specific tissues show certain peaks in clock genes like PRR can reveal more about the subtle nuances of each gene within the repressilator.

Few investigations into the circadian oscillator mechanisms in species other than A. thaliana have taken place; learning which genes are responsible for clock functions in other species will give more insight into the similarities and differences in clocks across plant species. [14]

The mechanistic details of each step in the plant biological clock repressilator system have yet to be fully understood. An understanding of these will give knowledge of clock function and, across species, increase understanding of the ecological and evolutionary functions of circadian oscillators. [7]

Additionally, identifying direct targets of PRR5, PRR7 and PRR9 that are not CCA1 and LHY will provide information about the molecular links from the PRRs to output genes like the flowering pathway and metabolism in mitochondria, which are CCA1-independent. [9]

See also

Related Research Articles

<i>Arabidopsis thaliana</i> species of flowering plant in the cabbage family Brassicaceae

Arabidopsis thaliana, the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. A. thaliana is considered a weed; it is found by roadsides and in disturbed land.

Circadian rhythm natural internal process that regulates the sleep-wake cycle

A circadian rhythm is a natural, internal process that regulates the sleep-wake cycle and repeats on each rotation of the Earth roughly every 24 hours. It can refer to any biological process that displays an endogenous, entrainable oscillation of about 24 hours. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria.

A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

Repressor

In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes into messenger RNA. An RNA-binding repressor binds to the mRNA and prevents translation of the mRNA into protein. This blocking or reducing of expression is called repression.

Cryptochrome Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins that are sensitive to blue light. They are found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and possibly also in the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the cryptic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

Florigen is the hypothesized hormone-like molecule responsible for controlling and/or triggering flowering in plants. Florigen is produced in the leaves, and acts in the shoot apical meristem of buds and growing tips. It is known to be graft-transmissible, and even functions between species. However, despite having been sought since the 1930s, the exact nature of florigen is still disputed.

ABC model of flower development

The ABC model of flower development is a scientific model of the process by which flowering plants produce a pattern of gene expression in meristems that leads to the appearance of an organ oriented towards sexual reproduction, a flower. There are three physiological developments that must occur in order for this to take place: firstly, the plant must pass from sexual immaturity into a sexually mature state ; secondly, the transformation of the apical meristem's function from a vegetative meristem into a floral meristem or inflorescence; and finally the growth of the flower's individual organs. The latter phase has been modelled using the ABC model, which aims to describe the biological basis of the process from the perspective of molecular and developmental genetics.

CLOCK

CLOCK or Clock is a gene encoding a basic helix-loop-helix-PAS transcription factor that is believed to affect both the persistence and period of circadian rhythms.

The repressilator is a genetic regulatory network consisting of at least one feedback loop with at least three genes, each expressing a protein that represses the next gene in the loop. In biological research, repressilators have been used to build cellular models and understand cell function. There are both artificial and naturally-occurring repressilators. Recently, the naturally-occurring repressilator clock gene circuit in Arabidopsis thaliana and mammalian systems have been studied.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Doubletime (dbt) also known as discs overgrown (dco) is a gene that encodes the double-time protein (DBT) in Drosophila melanogaster. The double-time protein is a kinase that phosphorylates PER protein that regulates the molecularly-driven, biological clock controlling circadian rhythm. The mammalian homolog of doubletime is casein kinase I epsilon. Different mutations in the dbt gene have been shown to cause lengthening, shortening, or complete loss in period of locomotor activity in flies. Drosophila and certain vertebrate Casein Kinase Id shows circadian function that has been evolutionary conserved over long time spans.

Timing of CAB expression 1 is a protein that in Arabidopsis thaliana is encoded by the TOC1 gene. TOC1 is also known as two-component response regulator-like APRR1.

Circadian Clock Associated 1 (CCA1) is a gene that is central to the circadian oscillator of angiosperms. It was first identified in Arabidopsis thaliana in 1993. CCA1 interacts with LHY and TOC1 to form the core of the oscillator system. CCA1 expression peaks at dawn. Loss of CCA1 function leads to a shortened period in the expression of many other genes.

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California.

LUX or Phytoclock1 (PCL1) is a gene that codes for LUX ARRHYTHMO, a protein necessary for circadian rhythms in Arabidopsis thaliana. LUX protein associates with Early Flowering 3 (ELF3) and Early Flowering 4 (ELF4) to form the Evening Complex (EC), a core component of the Arabidopsis repressilator model of the plant circadian clock. The LUX protein functions as a transcription factor that negatively regulates Pseudo-Response Regulator 9 (PRR9), a core gene of the Midday Complex, another component of the Arabidopsis repressilator model. LUX is also associated with circadian control of hypocotyl growth factor genes PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PHYTOCHROME INTERACTING FACTOR 5 (PIF5).

Andrew John McWalter Millar, FRS, FRSE is a Scottish chronobiologist, systems biologist, and molecular geneticist. Millar is a professor at The University of Edinburgh and also serves as its chair of systems biology. Millar is best known for his contributions to plant circadian biology; in the Steve Kay lab, he pioneered the use of luciferase imaging to identify circadian mutants in Arabidopsis. Additionally, Millar's group has implicated the ELF4 gene in circadian control of flowering time in Arabidopsis. Millar was elected to the Royal Society in 2012 and the Royal Society of Edinburgh in 2013.

A cytokinin signaling and response regulator protein is a plant protein that is involved in a two step cytokinin signaling and response regulation pathway.

The Late Elongated Hypocotyl gene (LHY), is an oscillating gene found in plants that functions as part of their circadian clock. LHY encodes components of mutually regulatory negative feedback loops with Circadian Clock Associated 1 (CCA1) in which overexpression of either results in dampening of both of their expression. This negative feedback loop affects the rhythmicity of multiple outputs creating a daytime protein complex. LHY was one of the first genes identified in the plant clock, along with TOC1 and CCA1. LHY and CCA1 have similar patterns of expression, which is capable of being induced by light. Single loss-of-function mutants in both genes result in seemingly identical phenotypes, but LHY cannot fully rescue the rhythm when CCA1 is absent, indicating that they may only be partially functionally redundant. Under constant light conditions, CCA1 and LHY double loss-of-function mutants fail to maintain rhythms in clock-controlled RNAs.

Transcription-translation feedback loop (TTFL), is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Dmitri Nusinow is an American chronobiologist who studies plant circadian rhythms. He was born on November 7, 1976 in Inglewood, California. He currently resides in St. Louis, and his research focus includes a combination of molecular, biochemical, genetic, genomic, and proteomic tools to discover the molecular connections between signaling networks, circadian oscillators, and specific outputs. By combining these methods, he hopes to apply the knowledge elucidated from the Arabidopsis model to other plant species.

References

  1. 1 2 Salomé, Patrice A.; McClung, C. Robertson (2004). "The Arabidopsis thaliana Clock". Journal of Biological Rhythms. 19 (5): 425–435. doi:10.1177/0748730404268112. PMID   15534322. S2CID   19023414.
  2. ↑ Boss, Paul K.; Bastow, Ruth M.; Mylne, Joshua S.; Dean, Caroline (2004-06-01). "Multiple Pathways in the Decision to Flower: Enabling, Promoting, and Resetting". The Plant Cell. 16 (suppl 1): S18–S31. doi:10.1105/tpc.015958. ISSN   1532-298X. PMC   2643402 . PMID   15037730.
  3. ↑ Alabadí, David; Oyama, Tokitaka; Yanovsky, Marcelo J.; Harmon, Franklin G.; Más, Paloma; Kay, Steve A. (2001-08-03). "Reciprocal Regulation Between TOC1 and LHY/CCA1 Within the Arabidopsis Circadian Clock". Science. 293 (5531): 880–883. doi:10.1126/science.1061320. ISSN   0036-8075. PMID   11486091. S2CID   8535547.
  4. ↑ Matsushika, Akinori (2000). "Circadian Waves of Expression of the APRR1/TOC1 Family of Pseudo-Response Regulators in Arabidopsis thaliana: Insight into the Plant Circadian Clock". Plant Cell Physiology. 41 (9): 1002–1012. doi: 10.1093/pcp/pcd043 . PMID   11100772.
  5. ↑ Pokhilko, Alexandra; Fernández, Aurora Piñas; Edwards, Kieron D.; Southern, Megan M.; Halliday, Karen J.; Millar, Andrew J. (2012-01-01). "The clock gene circuit in Arabidopsis includes a repressilator with additional feedback loops". Molecular Systems Biology. 8 (1): 574. doi:10.1038/msb.2012.6. ISSN   1744-4292. PMC   3321525 . PMID   22395476.
  6. ↑ Liu, Yi; Bell-Pedersen, Deborah (2017-04-27). "Circadian Rhythms in Neurospora crassa and Other Filamentous Fungi". Eukaryotic Cell. 5 (8): 1184–1193. doi:10.1128/EC.00133-06. ISSN   1535-9778. PMC   1539135 . PMID   16896204.
  7. 1 2 3 4 5 6 7 8 9 McClung, C. Robertson (2006-04-01). "Plant Circadian Rhythms". The Plant Cell. 18 (4): 792–803. doi:10.1105/tpc.106.040980. ISSN   1532-298X. PMC   1425852 . PMID   16595397.
  8. ↑ Alabadi, David; Oyama, Tokitaka; Yanovsky, Marcelo; Harmon, Franklin (2001). "Reciprocal regulation between TOC1 and LHY/CCA 1 within the Arabidopsis Circadian clock". Science. 293 (5531): 880–883. doi:10.1126/science.1061320. PMID   11486091. S2CID   8535547.
  9. 1 2 3 4 5 6 7 8 9 10 11 Nakamichi, Norihito; Kiba, Takatoshi; Henriques, Rossana; Mizuno, Takeshi; Chua, Nam-Hai; Sakakibara, Hitoshi (2010-03-01). "PSEUDO-RESPONSE REGULATORS 9, 7, and 5 Are Transcriptional Repressors in the Arabidopsis Circadian Clock". The Plant Cell. 22 (3): 594–605. doi:10.1105/tpc.109.072892. ISSN   1532-298X. PMC   2861452 . PMID   20233950.
  10. 1 2 Golembeski, Greg S.; Imaizumi, Takato (2015-01-01). "Photoperiodic Regulation of Florigen Function in Arabidopsis thaliana". The Arabidopsis Book. 13: e0178. doi:10.1199/tab.0178. PMC   4489636 . PMID   26157354.
  11. ↑ Hayama, Ryosuke; Sarid-Krebs, Liron; Richter, René; Fernández, Virginia; Jang, Seonghoe; Coupland, George (3 April 2017). "PSEUDO RESPONSE REGULATORs stabilize CONSTANS protein to promote flowering in response to day length". The EMBO Journal. 36 (7): 904–918. doi:10.15252/embj.201693907. ISSN   1460-2075. PMC   5376961 . PMID   28270524.
  12. ↑ Banks, Jo Ann; Nishiyama, Tomoaki; Hasebe, Mitsuyasu; Bowman, John L.; Gribskov, Michael; dePamphilis, Claude; Albert, Victor A.; Aono, Naoki; Aoyama, Tsuyoshi (2011-05-20). "The compact Selaginella genome identifies changes in gene content associated with the evolution of vascular plants". Science. 332 (6032): 960–963. doi:10.1126/science.1203810. ISSN   0036-8075. PMC   3166216 . PMID   21551031.
  13. ↑ Shim, Jae Sung; Kubota, Akane; Imaizumi, Takato (2017-01-01). "Circadian Clock and Photoperiodic Flowering in Arabidopsis: CONSTANS Is a Hub for Signal Integration". Plant Physiology. 173 (1): 5–15. doi:10.1104/pp.16.01327. ISSN   1532-2548. PMC   5210731 . PMID   27688622.
  14. ↑ Shim, Jae Shung; Imaizumi, Takato (2014). "Circadian Clock and Photoperiodic Response in Arabidopsis: From Seasonal Flowering to Redox Homeostasis". Biochemistry. 54 (2): 157–170. doi:10.1021/bi500922q. PMC   4303289 . PMID   25346271.
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