Degradation of Ndd1 by APC/C(Cdh1) generates a feed forward loop that times mitotic protein accumulation

• Published in: Nature communications Vol. 6; p. 7075
• Main Authors: Sajman, Julia, Zenvirth, Drora, Nitzan, Mor, Margalit, Hanah, Simpson-Lavy, Kobi J, Reiss, Yuval, Cohen, Itamar, Ravid, Tommer, Brandeis, Michael
• Format: Journal Article
• Language: English
• Published: England 11.05.2015
• Subjects: Cdh1 Proteins - genetics; Cdh1 Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Gene Expression Regulation, Fungal - physiology; Mitosis - physiology; Proteolysis; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723
• DOI: 10.1038/ncomms8075

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.