Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA.
Transcriptional feedback loops are central to the generation and maintenance of circadian rhythms. In animal systems as well as Neurospora, transcriptional repression is believed to occur by catalytic post-translational events. We report here in the Drosophila model two different mechanisms by which the circadian repressor PERIOD (PER) inhibits CLOCK/CYCLE (CLK/CYC)-mediated transcription. First, PER is recruited to circadian promoters, which leads to the nighttime decrease of CLK/CYC activity. This decrease is proportional to PER levels on DNA, and PER recruitment probably occurs via CLK. Then CLK is released from DNA and sequestered in a strong, approximately 1:1 PER-CLK off-DNA complex. The data indicate that the PER levels bound to CLK change dynamically and are important for repression, first on-DNA and then off-DNA. They also suggest that these mechanisms occur upstream of post-translational events, and that elements of this two-step mechanism likely apply to mammals.
Department of Biology, Howard Hughes Medical Institute, National Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts 02454, USA.
Jerome S
JS
Menet
Katharine C
KC
Abruzzi
Jennifer
J
Desrochers
Joseph
J
Rodriguez
Michael
M
Rosbash
D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000378:metabolism*; D004257:DNA Polymerase II / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D056950:Period Circadian Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding
C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; D056950:Period Circadian Proteins; D004247:DNA; D056926:CLOCK Proteins; D004257:DNA Polymerase II