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

Julia Sajman, Drora Zenvirth, Mor Nitzan, Hanah Margalit, Kobi J. Simpson-Lavy, Yuval Reiss, Itamar Cohen, Tommer Ravid and Michael Brandeis ()
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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
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8075

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