Role of PER-WDR5 interactions in the mammalian circadian clock

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Abstract
In the mammalian circadian clock, the transcription factor CLOCK/BMAL1 cycles between an active state recruiting co-activators like MLL1 and repressed states associated with PER1/2 and CRY1/2 clock proteins. The MLL1 complex component WDR5 was also found in a repressive PER complex. Here we show that WDR5 directly binds to the CRY binding domain (CBD) regions of PER1 and PER2. PER2 binds WDR5 via a WBM motif within the PER2/CRY interface, imposing competition between PER2/WDR5-, PER2/CRY- and RbBP5/WDR5 complexes. PER1 binds WDR5 predominantly via a WIN motif outside the CBD, enabling formation of trimeric PER1 WIN /WDR5/RbBP5 WBM - and PER1/WDR5/CRY complexes. WDR5 WIN site inhibitors weaken PER1/WDR5 interactions and impact cellular Bmal1- and Per2 expression dependent on the PER1 WIN motif, likely modulating the primary BMAL1/CLOCK/PER/CRY- and secondary BMAL1/REV-ERB/ROR circadian feedback loop. Together, our studies revealed a role of WDR5 as a direct PER interaction partner with critical differences between PER1 and PER2.
Funding Information
  • Deutsche Forschungsgemeinschaft (GRK2526/1/2-Project-ID 407023052)
  • Deutsche Forschungsgemeinschaft (SFB 1361-Project-ID 393547839)
  • Deutsche Forschungsgemeinschaft (GRK2526/1/2-Project-ID 407023052)
  • Deutsche Forschungsgemeinschaft (Emmy Noether project-ID 449991970)
  • Deutsche Forschungsgemeinschaft (SFB1551 project-ID 464588647)
  • Human Frontier Science Program
  • Molecular Life Sciences graduate program

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