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Degradation of Ndd1 by APC/CCdh1 generates a feed forward loop that times mitotic protein accumulation

Author

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  • Julia Sajman

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Drora Zenvirth

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Mor Nitzan

    (The Racah Institute of Physics, The Hebrew University of Jerusalem
    The Faculty of Medicine, The Hebrew University of Jerusalem)

  • Hanah Margalit

    (The Faculty of Medicine, The Hebrew University of Jerusalem)

  • Kobi J. Simpson-Lavy

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Yuval Reiss

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem
    The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Itamar Cohen

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Tommer Ravid

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

  • Michael Brandeis

    (The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem)

Abstract

Ndd1 activates the Mcm1–Fkh2 transcription factor to transcribe mitotic regulators. The anaphase-promoting complex/cyclosome activated by Cdh1 (APC/CCdh1) mediates the degradation of proteins throughout G1. Here we show that the APC/CCdh1 ubiquitinates Ndd1 and mediates its degradation, and that APC/CCdh1 activity suppresses accumulation of Ndd1 targets. We confirm putative Ndd1 targets and identify novel ones, many of them APC/CCdh1 substrates. The APC/CCdh1 thus regulates these proteins in a dual manner—both pretranscriptionally and post-translationally, forming a multi-layered feedforward loop (FFL). We predict by mathematical modelling and verify experimentally that this FFL introduces a lag between APC/CCdh1 inactivation at the end of G1 and accumulation of genes transcribed by Ndd1 in G2. This regulation generates two classes of APC/CCdh1 substrates, early ones that accumulate in S and late ones that accumulate in G2. Our results show how the dual state APC/CCdh1 activity is converted into multiple outputs by interactions between its substrates.

Suggested Citation

  • Julia Sajman & Drora Zenvirth & Mor Nitzan & Hanah Margalit & Kobi J. Simpson-Lavy & Yuval Reiss & Itamar Cohen & Tommer Ravid & Michael Brandeis, 2015. "Degradation of Ndd1 by APC/CCdh1 generates a feed forward loop that times mitotic protein accumulation," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8075
    DOI: 10.1038/ncomms8075
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