title: Degradation of Ndd1 by APC/C(Cdh1) generates a feed forward loop that times mitotic protein accumulation.
abstract: 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.
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Sajman
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
authors.forename: Drora
authors.initials: D
authors.lastname: Zenvirth
authors.affiliation: 1] The Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel [2] The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Nitzan
authors.affiliation: The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
authors.forename: Hanah
authors.initials: H
authors.lastname: Margalit
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
authors.forename: Kobi J
authors.initials: KJ
authors.lastname: Simpson-Lavy
authors.affiliation: 1] The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel [2] The Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem,, Jerusalem 9190401, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Reiss
authors.affiliation: The Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem,, Jerusalem 9190401, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Cohen
authors.affiliation: The Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem,, Jerusalem 9190401, Israel.
authors.forename: Tommer
authors.initials: T
authors.lastname: Ravid
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Brandeis
mesh_terms: D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C577583:CDH1 protein, S cerevisiae; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C118820:NDD1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors