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• W2000257273 abstract "We, and every other organism in the solar system, live in a profoundly rhythmic environment. The frequencies of these environmental cycles on Earth range from minutes to years, but for most organisms the dominant periodicity is that of the earth's rotation. A wide variety of organisms, including most eukaryotes and nearly all higher organisms, express circadian biological clocks that enable them to anticipate this particular environmental rhythmicity, and the output of these clocks are circadian rhythms. In fact, these cell-based clocks are so useful and their regulation so pervasive that for most living things the time of day that cells experience has almost everything to do with the subjective time dictated by the cell's internal clock and relatively little to do with whether it happens to be relatively warmer or cooler, or whether it is, just then, dark or light outside.For these clocks to be truly useful all year long in a variable and systematically changing environment, they must be robust, must be resettable by environmental cues, and must keep time equally well even though the ambient temperature or nutrition changes. True circadian clocks reflect the following necessities. The period length of the cycles organized by a circadian clock is close to but not equal to 24 h (circa dian); the cycles persist for many days in the absence of environmental cues; the phase of the rhythm (i.e. when, in real hours, the peaks and troughs in the cycle occur) is set by the last seen environmental time cues (lights on or off, or for most organisms a major temperature transition); the cycles persist through a normally noisy environment. Likewise, the period lengths are approximately the same if the average ambient temperature is at the warm or cool end of the physiological range, a property known as temperature compensation. Rhythms with these characteristics, circadian rhythms, are widely believed to share a common molecular basis across wide phylogenetic groups of organisms. Long period rhythms (12 to ∼100 h) lacking one or more of these characteristics are not circadian rhythms; such rhythms are not infrequently found, particularly in systems where circadian regulation has been impaired, but they generally reflect organism-specific biology and are not thought to be informative regarding the common molecular bases of circadian rhythms.The circadian oscillator is viewed as the biochemical feedback loop(s) underlying circadian rhythmicity per se, and the circadian system is taken to include the oscillator and the aspects of cell and organism physiology (including driven circuits and feedback loops that acquire daily periodicity via output from the circadian oscillator) that together produce the overt metabolic and behavioral rhythms in the living organism. The biochemical oscillators underlying these rhythms are based at the level of the cell in all organisms exhibiting circadian rhythms, and at least conceptually, the problem of understanding biological timekeeping can be subdivided into three general questions. What are the molecular components of the core feedback loop(s) and how do they work together to keep time? How is such a circadian system entrained to light and temperature cycles in the real world? Given an entrainable clock mechanism, how and through what pathways does it act to regulate the metabolism of the cell in which it operates, and thereby the physiology and behavior of the whole organism?The filamentous fungus Neurospora crassa rose to prominence as a circadian model system because of the genetic and molecular tractability of its clock, as well as for its overall similarity to the animal circadian systems (chiefly Drosophila) being dissected at the same time (1Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar). It has served as one of the most significant and durable model systems in this field, playing a central part in both framing the questions and providing the answers to the central questions of chronobiology. The Neurospora genome of 10,620 genes is documented by a >16-fold sequence coverage supported by sophisticated bioinformatics tools; targeted gene replacements are routine with systematic efforts to delete all genes well under way (2Colot H. Park G. Jones J. Turner G. Borkovich K. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 10352-10357Crossref PubMed Scopus (845) Google Scholar); availability of inexpensive whole genome microarrays is fostering transcriptional profiling; and a detailed single nucleotide polymorphism map combined with routine transformation using regulatable promoters has greatly smoothed the path of cloning and analysis of genes arising from screens.Known Components of Neurospora Circadian Feedback LoopTranscription and translation-based negative feedback loops are central elements in eukaryotic circadian clocks (1Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar, 3Dunlap J.C. Dunlap J.C. Loros J.J. Decoursey P. Chronobiology: Biological Timekeeping. Sinauer Associates, Sunderland, MA2004: 212-253Google Scholar, 4Young M.W. Kay S.A. Nat. Rev. Genet. 2001; 2: 702-715Crossref PubMed Scopus (920) Google Scholar, 5Hirayama J. Sassone-Corsi P. Curr. Opin. Genet. Dev. 2005; 15: 548-556Crossref PubMed Scopus (88) Google Scholar, 6Bell-Pedersen D. Cassone V.M. Earnest D.J. Golden S.S. Hardin P.E. Thomas T.L. Zoran M.J. Nat. Rev. Genet. 2005; 6: 544-556Crossref PubMed Scopus (1002) Google Scholar, 7Heintzen C. Liu Y. Adv. Genet. 2006; (in press)Google Scholar). In animals and fungi these feedback loops have a single transcription step in which a heterodimeric transcriptional activator (a positive element) promotes expression of a gene encoding a protein (the negative element in the loop) that depresses the activity of the activator. In all circadian systems there are additional feedback loops that are nested around the core, often connecting output to input or providing additional levels of control that can fine tune the oscillator. When this central feedback loop is first disabled by mutation and then genetic background, growth conditions, and nutrition are carefully. adjusted, noncircadian rhythms in growth can usually be detected (e.g. Ref. 8Loros J.J. Feldman J.F. J. Biol. Rhythms. 1986; 1: 187-198Crossref PubMed Scopus (131) Google Scholar). Although there is continued interest in whether these cryptic rhythms may inform research on the circadian system, most are poorly characterized molecularly (an exception being Ref. 9dePaula R.M. Lewis Z.A. Greene A.V. Seo K.S. Morgan L.W. Vitalini M.W. Bennett L. Gomer R.H. Bell-Pedersen D. J. Biol. Rhythms. 2006; 21: 159-168Crossref PubMed Scopus (45) Google Scholar), and readers are referred elsewhere for a fuller description of them (6Bell-Pedersen D. Cassone V.M. Earnest D.J. Golden S.S. Hardin P.E. Thomas T.L. Zoran M.J. Nat. Rev. Genet. 2005; 6: 544-556Crossref PubMed Scopus (1002) Google Scholar, 10Aronson B.D. Johnson K.A. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7683-7687Crossref PubMed Scopus (193) Google Scholar, 11Merrow M. Bruner M. Roenneberg T. Nature. 1999; 399: 584-586Crossref PubMed Scopus (192) Google Scholar, 12Lakin-Thomas P.L. Trends Genet. 2000; 16: 135-142Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 13Christensen M. Falkeid G. Hauge I. Loros J.J. Dunlap J.C. Lillo C. Ruoff P. J. Biol. Rhythms. 2004; 19: 280-286Crossref PubMed Scopus (59) Google Scholar, 14Lakin-Thomas P.L. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 4469-4474Crossref PubMed Scopus (29) Google Scholar, 15Dunlap J.C. Loros J.J. J. Biol. Rhythms. 2004; 19: 414-424Crossref PubMed Scopus (170) Google Scholar).Central components of the transcription-translation-based circadian negative feedback loop in Neurospora include two negative elements, the proteins FREQUENCY (FRQ) (1Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar, 10Aronson B.D. Johnson K.A. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7683-7687Crossref PubMed Scopus (193) Google Scholar, 16Aronson B. Johnson K. Loros J.J. Dunlap J.C. Science. 1994; 263: 1578-1584Crossref PubMed Scopus (505) Google Scholar, 17Crosthwaite S.C. Dunlap J.C. Loros J.J. Science. 1997; 276: 763-769Crossref PubMed Scopus (436) Google Scholar) and FRQ-RELATED HELICASE (FRH) (18Cheng P. He Q. He Q. Wang L. Liu Y. Genes Dev. 2005; 19: 234-241Crossref PubMed Scopus (155) Google Scholar), and two positive elements, WHITE COLLAR-1 (WC-1) and WHITE COLLAR-2 (WC-2) (17Crosthwaite S.C. Dunlap J.C. Loros J.J. Science. 1997; 276: 763-769Crossref PubMed Scopus (436) Google Scholar). FRQ and FRH thus perform a function like that of the PERs and CRYs in the mammalian clock, and WC-1 and WC-2 form a unit and function like the BMAL1 and CLOCK/NPAS2 heterodimers in mammals, but more of this later. In addition to these core players, there are a number of proteins with supporting roles, the various kinases and phosphatases that modulate activities and interactions among the core as well as the elements of the protein degradation pathway that are required for the daily turnover of FRQ. Inherent to the oscillator is the daily self-sustained rhythm in the synthesis and turnover of frq mRNA and FRQ proteins, so progress of the Neurospora oscillator, like other eukaryotic clocks, is characterized by cycles in the levels of transcript and protein. Loss-of-function mutations in frq (10Aronson B.D. Johnson K.A. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7683-7687Crossref PubMed Scopus (193) Google Scholar), wc-1 (17Crosthwaite S.C. Dunlap J.C. Loros J.J. Science. 1997; 276: 763-769Crossref PubMed Scopus (436) Google Scholar), or wc-2 (19Collett M. Dunlap J.C. Loros J.J. Mol. Cell. Biol. 2001; 21: 2619-2628Crossref PubMed Scopus (32) Google Scholar) result in loss of circadian rhythmicity; partial loss-of-function mutations in wc-2 (19Collett M. Dunlap J.C. Loros J.J. Mol. Cell. Biol. 2001; 21: 2619-2628Crossref PubMed Scopus (32) Google Scholar) or frq (10Aronson B.D. Johnson K.A. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7683-7687Crossref PubMed Scopus (193) Google Scholar) can result in significant period length changes (yielding periods from 16 to 35 h), in addition to partial loss of temperature and nutritional compensation of the clock. Environmental signals such as changes in ambient light and temperature reset the Neurospora clock by changing the levels of frq mRNA and FRQ protein (20Crosthwaite S.C. Loros J.J. Dunlap J.C. Cell. 1995; 81: 1003-1012Abstract Full Text PDF PubMed Scopus (300) Google Scholar, 21Liu Y. Merrow M. Loros J.J. Dunlap J.C. Science. 1998; 281: 825-829Crossref PubMed Scopus (181) Google Scholar) as further outlined below.frq Transcripts and FRQ Proteins, Negative Elements in the Cyclefrq was identified by genetics screens in the early 1970s (22Feldman J.F. Hoyle M. Genetics. 1973; 75: 605-613Crossref PubMed Google Scholar), and molecular dissection of the Neurospora circadian oscillator can be traced to the positional cloning of frq in the mid-1980s. Subsequent progress on the molecular basis of rhythmicity has largely been tied to identification and analysis of the genes and proteins that regulate its synthesis, action, and destruction. Early work on the frq transcripts based on the sequence of cDNA fragments (10Aronson B.D. Johnson K.A. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7683-7687Crossref PubMed Scopus (193) Google Scholar) were consistent with a simple transcription unit, but inconsistencies in these data foreshadowed identification of the frq antisense message (23Kramer C. Loros J.J. Dunlap J.C. Crosthwaite S.K. Nature. 2003; 421: 948-952Crossref PubMed Scopus (126) Google Scholar). This nearly 5-kb antisense transcript (qrf, for frq backwards) arises from the frq locus, beginning from a promoter 3′ to the region necessary for complementation of frq null mutations. qrf appears not to encode a protein but is rhythmically expressed at low levels with a peak phase opposite to that of frq, is light-induced, and appears to play a role in ensuring precise entrainment to light/dark cues (23Kramer C. Loros J.J. Dunlap J.C. Crosthwaite S.K. Nature. 2003; 421: 948-952Crossref PubMed Scopus (126) Google Scholar). frq also has one of the most complex transcription units seen in a lower eukaryote; frq transcripts arise from multiple promoters, and each frq transcript can be spliced in a complex manner that is influenced by ambient temperature (Fig. 1). In this way, temperature-influenced splicing determines whether long (989 amino acids) or short (889 amino acids) FRQ proteins are synthesized (24Garceau N. Liu Y. Loros J.J. Dunlap J.C. Cell. 1997; 89: 469-476Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Both forms are needed for robust rhythmicity. At temperatures in the low end of the physiological range (<22 °C) predominantly short FRQ is used and less overall FRQ is needed, whereas at higher temperatures (>26 °C) the large form and higher overall levels are used (25Liu Y. Garceau N. Loros J.J. Dunlap J.C. Cell. 1997; 89: 477-486Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar); strains expressing only one form show small but statistically significant differences in period length (25Liu Y. Garceau N. Loros J.J. Dunlap J.C. Cell. 1997; 89: 477-486Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar), although the biological significance of these differences is clouded by accompanying changes in dosage. Despite these distinguishable physiological functions, half-lives of the two FRQ isoforms are not different and no distinctions in molecular activities are known. The temperature-modulated translation is governed by upstream open reading frames in the 5′-untranslated region (UTR) 2The abbreviations used are: UTR, untranslated region; FFC, FRQ-FRH complex; WCC, white collar complex; CKI, casein kinase I. of frq (26Colot H.V. Loros J.J. Dunlap J.C. Mol. Biol. Cell. 2005; 16: 5563-5571Crossref PubMed Scopus (91) Google Scholar, 27Diernfellner A.C. Schafmeier T. Merrow M.W. Brunner M. Genes Dev. 2005; 19: 1968-1973Crossref PubMed Scopus (91) Google Scholar). Although this complicated temperature regulation of forms and amounts does not play a role in temperature compensation, it does seem to help in keeping the phase of the rhythm steady across a temperature range. 3A. Diernfellner, H. Colot, J. Dunlap, and M. Brunner, manuscript in preparation. Temperature compensation appears to derive from a balancing of synthesis and turnover of components, especially FRQ (28Ruoff P. Loros J.J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 17681-17686Crossref PubMed Scopus (104) Google Scholar).FRQ undergoes a daily cycle of phosphorylations that greatly influence its activities. As soon as FRQ appears, it is phosphorylated by one of several kinases including casein kinase I (CKI), CKII, and calcium/calmodulin-dependent kinase (29Yang Y. Cheng P. Liu Y. Genes Dev. 2002; 16: 994-1006Crossref PubMed Scopus (119) Google Scholar, 30Yang Y. Cheng P. Qiyang Q. He Q. Wang L. Liu Y. Mol. Cell. Biol. 2003; 23: 6221-6228Crossref PubMed Scopus (75) Google Scholar, 31Yang Y. Cheng P. Zhi G. Liu Y. J. Biol. Chem. 2001; 276: 41064-41072Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 32Gorl M. Merrow M. Huttner B. Johnson J. Roenneberg T. Brunner M. EMBO J. 2001; 20: 7074-7084Crossref PubMed Scopus (130) Google Scholar), and this phosphorylation plays a central role in the feedback loop. Recent work has also shown that FRQ can associate with and be phosphorylated by the Neurospora checkpoint kinase 2 (PRD-4), an event that renders the circadian cycle sensitive to resetting by DNA-damaging agents (33Pregueiro A. Liu Q. Baker C. Dunlap J.C. Loros J.J. Science. 2006; 313: 644-649Crossref PubMed Scopus (107) Google Scholar). This suggests that phosphorylation of FRQ may be the common entry point for clock effects of a variety of environmental agents. The effects of phosphorylation are varied. It is apparent on reflection that for the feedback loop to cycle effectively, FRQ must turn over almost completely once per cycle, and the chief determinant of when this happens is its phosphorylation status (28Ruoff P. Loros J.J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 17681-17686Crossref PubMed Scopus (104) Google Scholar, 34Liu Y. Loros J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 234-239Crossref PubMed Scopus (165) Google Scholar). In this manner the kinases that act on FRQ play a major role in determining the period length of the clock, and alleles of FRQ that are more stable (such as FRQ7) (28Ruoff P. Loros J.J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 17681-17686Crossref PubMed Scopus (104) Google Scholar, 35Dunlap J.C. Feldman J.F. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 1096-1100Crossref PubMed Scopus (54) Google Scholar) have long period lengths. Both kinase inhibitors and mutation of FRQ to alter normal sites of its phosphorylation can greatly increase the period of the cycles (32Gorl M. Merrow M. Huttner B. Johnson J. Roenneberg T. Brunner M. EMBO J. 2001; 20: 7074-7084Crossref PubMed Scopus (130) Google Scholar, 34Liu Y. Loros J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 234-239Crossref PubMed Scopus (165) Google Scholar, 36Schafmeier T. Haase A. Kaldi K. Scholz J. Fuchs M. Brunner M. Cell. 2005; 122: 235-246Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Phosphorylation of FRQ can also influence its interactions with the white collar complex (WCC) (29Yang Y. Cheng P. Liu Y. Genes Dev. 2002; 16: 994-1006Crossref PubMed Scopus (119) Google Scholar). In general, the importance of FRQ phosphorylation to the operation of the clock has been established, but the phosphorylation pattern is quite complex and probably processive. There are a number of distinguishable phosphorylated forms of both FRQ proteins, and the determination of how each modification affects activities and interactions is an important goal of future work.FRH, an RNA Helicase Essential for the ClockThe other required negative element, FRH, is likely to be an RNA helicase based on its sequence. This 1106-amino acid protein was identified as a protein that co-purifies with FRQ (18Cheng P. He Q. He Q. Wang L. Liu Y. Genes Dev. 2005; 19: 234-241Crossref PubMed Scopus (155) Google Scholar), and an RNA interference-mediated knockdown of its activity confirmed that it is essential for rhythmicity and also for life. A member of the SKI2 subfamily of RNA helicases, FRH contains a DEAD/DEAH box and helicase C domains, and its closest homolog is the Mtr4/Dob1 helicase from Saccharomyces, a component of the exosome complex of 3′–5′-exonucleases involved in RNA maturation and quality control (37Mitchell P. Tollervey D. Mol. Cell. 2003; 11: 1405-1413Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 38LaCava J. Houseley J. Saveanu C. Petfalski E. Thompson E. Jacquier A. Tollervey D. Cell. 2005; 121: 713-724Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar). FRH is not a trivial or transient partner; nearly all FRQ in the cell is complexed with FRH, although much of the cell's FRH pool is not bound to FRQ. This FRQ-FRH complex (FFC) (7Heintzen C. Liu Y. Adv. Genet. 2006; (in press)Google Scholar) is both nuclear and cytoplasmic and most FFC is not bound to the WCC. Next to nothing is known concerning the nature of the role of FRH, whether this entails RNA binding, or how it acts. So far the genetics of FRH is limited to the single knockdown strain, so further genetic analysis of this important protein, as well as the obvious experiments to see whether it is binding an RNA, will be of interest.WC-1 and WC-2, Positive Elements in the CycleWC-1 and WC-2 are true transcription factors that contain acidic and polyglutamine transcriptional activation domains, GATA-type zinc finger DNA-binding domains, and the protein interaction domains known as PAS domains (39Lee K. Loros J.J. Dunlap J.C. Science. 2000; 289: 107-110Crossref PubMed Scopus (283) Google Scholar, 40Ballario P. Talora C. Galli D. Linden H. Macino G. Mol. Microbiol. 1998; 29: 719-729Crossref PubMed Scopus (150) Google Scholar, 41Cheng P. Yang Y. Gardner K.H. Liu Y. Mol. Cell. Biol. 2002; 22: 517-524Crossref PubMed Scopus (135) Google Scholar). These proteins are found together as a complex consisting of one copy each of WC-1 and WC-2 (WCC) (41Cheng P. Yang Y. Gardner K.H. Liu Y. Mol. Cell. Biol. 2002; 22: 517-524Crossref PubMed Scopus (135) Google Scholar, 42Linden H. Ballario P. Arpaia G. Macino G. Adv. Genet. 1999; 41: 35-54Crossref PubMed Scopus (29) Google Scholar, 43Denault D.L. Loros J.J. Dunlap J.C. EMBO J. 2001; 20: 109-117Crossref PubMed Scopus (150) Google Scholar); WC-1 is predominantly nuclear but WC-2 is seen throughout the cell. Such heterodimeric complexes are typical of fungal and animal circadian feedback loops (1Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar, 17Crosthwaite S.C. Dunlap J.C. Loros J.J. Science. 1997; 276: 763-769Crossref PubMed Scopus (436) Google Scholar, 44Dunlap J.C. Science. 1998; 280: 1548-1549Crossref PubMed Scopus (84) Google Scholar), and in fact the heteromeric complex in Neurospora was the first such to be described. The complex in mammals includes BMAL1 and CLOCK, and BMAL1, a sequence and functional homolog of WC-1 (39Lee K. Loros J.J. Dunlap J.C. Science. 2000; 289: 107-110Crossref PubMed Scopus (283) Google Scholar), plays an identical role in the cognate mammalian clock as noted above. The WCC can assemble and bind to the frq promoter in vitro (45Froehlich A.C. Loros J.J. Dunlap J.C. Science. 2002; 297: 815-819Crossref PubMed Scopus (401) Google Scholar, 46Froehlich A.C. Loros J.J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5914-5919Crossref PubMed Scopus (144) Google Scholar, 47He Q. Shu H. Cheng P. Chen S. Wang L. Liu Y. J. Biol. Chem. 2005; 280: 17526-17532Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) and is the chief regulator of frq expression; null mutants of either wc-1 or wc-2 display low levels of frq mRNA and FRQ (17Crosthwaite S.C. Dunlap J.C. Loros J.J. Science. 1997; 276: 763-769Crossref PubMed Scopus (436) Google Scholar, 41Cheng P. Yang Y. Gardner K.H. Liu Y. Mol. Cell. Biol. 2002; 22: 517-524Crossref PubMed Scopus (135) Google Scholar, 48Collett M.A. Garceau N. Dunlap J.C. Loros J.J. Genetics. 2002; 160: 149-158Crossref PubMed Google Scholar, 49He Q. Cheng P. Yang Y. Wang L. Gardner K. Liu Y. Science. 2002; 297: 840-842Crossref PubMed Scopus (341) Google Scholar). This heterodimer also functions as the principle photoreceptor in the cell by virtue of an FAD chromophore bound to WC-1 (45Froehlich A.C. Loros J.J. Dunlap J.C. Science. 2002; 297: 815-819Crossref PubMed Scopus (401) Google Scholar, 49He Q. Cheng P. Yang Y. Wang L. Gardner K. Liu Y. Science. 2002; 297: 840-842Crossref PubMed Scopus (341) Google Scholar) and in that role, exclusive of any clock function, is responsible for light responses seen for several percent of the genome (50Lewis Z.A. Correa A. Schwerdtfeger C. Link K.L. Xie X. Gomer R.H. Thomas T. Ebbole D.J. Bell-Pedersen D. Mol. Microbiol. 2002; 45: 917-931Crossref PubMed Scopus (83) Google Scholar).WC-1 is 1167 amino acids long (39Lee K. Loros J.J. Dunlap J.C. Science. 2000; 289: 107-110Crossref PubMed Scopus (283) Google Scholar, 42Linden H. Ballario P. Arpaia G. Macino G. Adv. Genet. 1999; 41: 35-54Crossref PubMed Scopus (29) Google Scholar) and is thought to always act with WC-2 as a complex. Like FRQ, the expression of WC-1 is complex, with multiple promoters and splice forms (51Kaldi K. Gonzalez B.H. Brunner M. EMBO Rep. 2006; 7: 199-204Crossref PubMed Scopus (51) Google Scholar) 4W. Belden, J. Loros, and J. Dunlap, manuscript in preparation. ; it shows a low amplitude rhythm in expression levels, but unlike FRQ, WC-1 expression is regulated post-transcriptionally (probably at the level of WCC assembly or turnover) through a complex mechanism involving FRQ (39Lee K. Loros J.J. Dunlap J.C. Science. 2000; 289: 107-110Crossref PubMed Scopus (283) Google Scholar, 52Schafmeier T. Kaldi K. Diernfellner A. Mohr C. Brunner M. Genes Dev. 2006; 20: 297-306Crossref PubMed Scopus (86) Google Scholar). As a central player in the clock, WC-1 is regulated by a host of factors including phosphorylation (39Lee K. Loros J.J. Dunlap J.C. Science. 2000; 289: 107-110Crossref PubMed Scopus (283) Google Scholar, 52Schafmeier T. Kaldi K. Diernfellner A. Mohr C. Brunner M. Genes Dev. 2006; 20: 297-306Crossref PubMed Scopus (86) Google Scholar, 53Arpaia G. Cerri F. Baima S. Macino G. Mol. Gen. Genet. 1999; 262: 314-322Crossref PubMed Scopus (58) Google Scholar), protein-protein interactions (41Cheng P. Yang Y. Gardner K.H. Liu Y. Mol. Cell. Biol. 2002; 22: 517-524Crossref PubMed Scopus (135) Google Scholar, 43Denault D.L. Loros J.J. Dunlap J.C. EMBO J. 2001; 20: 109-117Crossref PubMed Scopus (150) Google Scholar), and environmentally induced changes in secondary structure (45Froehlich A.C. Loros J.J. Dunlap J.C. Science. 2002; 297: 815-819Crossref PubMed Scopus (401) Google Scholar, 49He Q. Cheng P. Yang Y. Wang L. Gardner K. Liu Y. Science. 2002; 297: 840-842Crossref PubMed Scopus (341) Google Scholar). WC-1 is needed for FRQ and WC-2 to interact and also self-associates to some degree (54Cheng P. Yang Y. Wang L. He Q. Liu Y. J. Biol. Chem. 2003; 278: 3801-3808Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). In addition to the two PAS domains that play a role in protein-protein interactions, WC-1 contains a LOV domain, a subclass of PAS domains associated with proteins that sense light, oxygen, and voltage, and this domain mediates the activation of WC-1 activity by light (45Froehlich A.C. Loros J.J. Dunlap J.C. Science. 2002; 297: 815-819Crossref PubMed Scopus (401) Google Scholar). This light-induced activation of WC-1, which results in rapid and massive transcription of frq, provides the mechanism for clock resetting by light (20Crosthwaite S.C. Loros J.J. Dunlap J.C. Cell. 1995; 81: 1003-1012Abstract Full Text PDF PubMed Scopus (300) Google Scholar), and this resetting mechanism (light-mediated transcriptional induction of a negative element in the clock loop) is also used in mammals (55Shigeyoshi Y. Taguchi K. Yamamoto S. Takeida S. Yan L. Tei H. Moriya S. Shibata S. Loros J.J. Dunlap J.C. Okamura H. Cell. 1997; 91: 1043-1053Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar).WC-2 has a transcriptional activation domain, a single PAS domain, and a zinc finger DNA-binding domain. More abundant than WC-1, WC-2 is predominantly in the nucleus (43Denault D.L. Loros J.J. Dunlap J.C. EMBO J. 2001; 20: 109-117Crossref PubMed Scopus (150) Google Scholar), and the amount of protein does not appear to be acutely regulated (43Denault D.L. Loros J.J. Dunlap J.C. EMBO J. 2001; 20: 109-117Crossref PubMed Scopus (150) Google Scholar, 56Schwerdtfeger C. Linden H. Eur. J. Biochem. 2000; 267: 414-422Crossref PubMed Scopus (83) Google Scholar). WC-2, however, mediates the interactions between the regulated components in the clock cycle by complexing with WC-1 and with FRQ, consistent with the model in which FRQ acts to depress the level of its own transcript by interfering with the activation of the frq gene by the WCC (19Collett M. Dunlap J.C. Loros J.J. Mol. Cell. Biol. 2001; 21: 2619-2628Crossref PubMed Scopus (32) Google Scholar, 36Schafmeier T. Haase A. Kaldi K. Scholz J. Fuchs M. Brunner M. Cell. 2005; 122: 235-246Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 43Denault D.L. Loros J.J. Dunlap J.C. EMBO J. 2001; 20: 109-117Crossref PubMed Scopus (150) Google Scholar, 46Froehlich A.C. Loros J.J. Dunlap J.C. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5914-5919Crossref PubMed Scopus (144) Google Scholar). WC-1 and FRQ do not interact in the absence of WC-2 nor is DNA required for the interactions. Partially functional allelic versions of WC-2 have been useful in dissecting the differing roles of the protein in light and clock regulation. Some WC-2 variants clearly deficient in promoting light-induced gene expression show little if any defects in the light induction of frq (48Collett M.A. Garceau N. Dunlap J.C. Loros J.J. Genetics. 2002; 160: 149-158Crossref PubMed Google Scholar) indicating that the light signal transduction pathway cannot be as simple as WCC activation of all light-induced genes.How It All Works: Molecular Events in Neurospora Circadian CycleFor almost two decades research on the Neurospora clock contributed to and has been informed by the model of eukaryotic circadian clocks in which the daily translation of proteins is central to the oscillator (e.g. Ref. 35Dunlap J.C. Feldman J.F. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 1096-1100Crossref PubMed Scopus (54) Google Scholar); work on Neurospora was the first to experimentally test this model and prove the importance of daily transcription in this cycle (16Aronson B. Johnson K. Loros J.J. Dunlap J.C. Science. 1994; 263: 1578-1584Crossref PubMed Scopus (505) Google Scholar). Although in broad outline the model is still valid, recent work is beginning to flesh out the mechanism in pleasing detail. Fig. 2 serves as a guide for following the events within the Neurospora free running clock cycle starting from the left, the subjective morning.FIGURE 2Interlocked positive and negative feedback loops in the Neurospora clock. The top shows how the levels of frq mRNA, FRQ, and WC-1 proteins oscillate through time over one and a half cycles in constant darkness; subjective day (0–12, light bar) and subjective night (12–24/0, dark bar) are sh" @default.
• W2000257273 created "2016-06-24" @default.
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• W2000257273 title "Proteins in the Neurospora Circadian Clockworks" @default.
• W2000257273 cites W12596212 @default.
• W2000257273 cites W1492572309 @default.
• W2000257273 cites W1519373750 @default.
• W2000257273 cites W1530371171 @default.
• W2000257273 cites W1571815557 @default.
• W2000257273 cites W1589862831 @default.
• W2000257273 cites W1976971664 @default.
• W2000257273 cites W1979385177 @default.
• W2000257273 cites W1980988105 @default.
• W2000257273 cites W1983373264 @default.
• W2000257273 cites W1984709672 @default.
• W2000257273 cites W1985078116 @default.
• W2000257273 cites W1986496789 @default.
• W2000257273 cites W1988309554 @default.
• W2000257273 cites W1994880500 @default.
• W2000257273 cites W1998418064 @default.
• W2000257273 cites W1998999712 @default.
• W2000257273 cites W2000660632 @default.
• W2000257273 cites W2003725356 @default.
• W2000257273 cites W2005811101 @default.
• W2000257273 cites W2006280763 @default.
• W2000257273 cites W2007158191 @default.
• W2000257273 cites W2011485738 @default.
• W2000257273 cites W2025817597 @default.
• W2000257273 cites W2033758706 @default.
• W2000257273 cites W2039931639 @default.
• W2000257273 cites W2042068133 @default.
• W2000257273 cites W2046290772 @default.
• W2000257273 cites W2056296605 @default.
• W2000257273 cites W2057522076 @default.
• W2000257273 cites W2060424984 @default.
• W2000257273 cites W2061311715 @default.
• W2000257273 cites W2062526657 @default.
• W2000257273 cites W2070672002 @default.
• W2000257273 cites W2070856611 @default.
• W2000257273 cites W2072766765 @default.
• W2000257273 cites W2075873641 @default.
• W2000257273 cites W2079810511 @default.
• W2000257273 cites W2082958905 @default.
• W2000257273 cites W2096436921 @default.
• W2000257273 cites W2098165433 @default.
• W2000257273 cites W2099799645 @default.
• W2000257273 cites W2100391534 @default.
• W2000257273 cites W2102142621 @default.
• W2000257273 cites W2102492814 @default.
• W2000257273 cites W2106802176 @default.
• W2000257273 cites W2107478358 @default.
• W2000257273 cites W2114417962 @default.
• W2000257273 cites W2118514829 @default.
• W2000257273 cites W2119649830 @default.
• W2000257273 cites W2121743466 @default.
• W2000257273 cites W2131203140 @default.
• W2000257273 cites W2131652510 @default.
• W2000257273 cites W2134236962 @default.
• W2000257273 cites W2140988328 @default.
• W2000257273 cites W2147022672 @default.
• W2000257273 cites W2149811710 @default.
• W2000257273 cites W2154416833 @default.
• W2000257273 cites W2155265122 @default.
• W2000257273 cites W2155450177 @default.
• W2000257273 cites W2164653529 @default.
• W2000257273 cites W2171541875 @default.
• W2000257273 cites W2216046488 @default.
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