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

Julia Sajman1, Drora Zenvirth1, Mor Nitzan2

  • 1The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

Nature Communications
|May 12, 2015
PubMed

Insights

The anaphase-promoting complex/cyclosome (APC/C(Cdh1)) degrades Ndd1, a key regulator of mitotic genes. This dual regulation creates a feedforward loop, delaying gene expression until G2 and generating distinct substrate classes.

Area of Science:

  • Cell Cycle Regulation
  • Molecular Biology
  • Gene Expression Control

Background:

  • Ndd1 is a transcription factor that activates mitotic regulators.
  • The anaphase-promoting complex/cyclosome activated by Cdh1 (APC/C(Cdh1)) degrades proteins during the G1 phase.
  • Understanding the interplay between Ndd1 and APC/C(Cdh1) is crucial for cell cycle progression.

Purpose of the Study:

  • To investigate the role of APC/C(Cdh1) in regulating Ndd1.
  • To identify Ndd1 targets and determine if they are also APC/C(Cdh1) substrates.
  • To elucidate the regulatory mechanism of a multi-layered feedforward loop involving Ndd1 and APC/C(Cdh1).

Main Methods:

  • Ubiquitination assays to demonstrate Ndd1 degradation by APC/C(Cdh1).
  • Quantitative analysis of Ndd1 target gene expression.
  • Mathematical modeling to predict the timing of gene accumulation.
  • Experimental validation of model predictions.

Main Results:

  • APC/C(Cdh1) ubiquitinates and degrades Ndd1, suppressing the accumulation of its targets.
  • Novel Ndd1 targets were identified, many of which are also APC/C(Cdh1) substrates.
  • A multi-layered feedforward loop (FFL) was established, regulating genes both pre- and post-translationally.
  • The FFL introduces a temporal lag, separating early (S phase) and late (G2 phase) accumulating APC/C(Cdh1) substrates.

Conclusions:

  • APC/C(Cdh1) controls Ndd1 levels and its target gene expression, establishing a dual regulatory mechanism.
  • The identified FFL generates distinct temporal outputs, classifying APC/C(Cdh1) substrates into early and late accumulators.
  • This intricate regulatory network ensures precise control over mitotic gene expression through coordinated pre- and post-translational events.

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