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, Michael Brandeis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Ndd1 activates the Mcm1-Fkh2 transcription factor to transcribe mitotic regulators. The anaphase-promoting complex/cyclosome activated by Cdh1 (APC/C Cdh1) mediates the degradation of proteins throughout G1. Here we show that the APC/C Cdh1 ubiquitinates Ndd1 and mediates its degradation, and that APC/C Cdh1 activity suppresses accumulation of Ndd1 targets. We confirm putative Ndd1 targets and identify novel ones, many of them APC/C Cdh1 substrates. The APC/C Cdh1 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/C Cdh1 inactivation at the end of G1 and accumulation of genes transcribed by Ndd1 in G2. This regulation generates two classes of APC/C Cdh1 substrates, early ones that accumulate in S and late ones that accumulate in G2. Our results show how the dual state APC/C Cdh1 activity is converted into multiple outputs by interactions between its substrates.

Original languageAmerican English
Article number7075
JournalNature Communications
StatePublished - 11 May 2015

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