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Review
. 2010 Oct 1;9(19):3904-12.
doi: 10.4161/cc.9.19.13585. Epub 2010 Oct 11.

APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity

Xinxian Qiao  1 , Liyong Zhang, Armin M Gamper, Takeo Fujita, Yong Wan
Affiliations
Review

APC/C-Cdh1: from cell cycle to cellular differentiation and genomic integrity

Xinxian Qiao et al. Cell Cycle. .

Abstract

Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that _targets various substrates for proteolysis inside and outside of the cell cycle. The activation of APC/C is dependent on two WD-40 domain proteins, Cdc20 and Cdh1. While APC/Cdc20 principally regulates mitotic progression, APC/Cdh1 shows a broad spectrum of substrates in and beyond cell cycle. In the past several years, numerous biochemical and mouse genetic studies have greatly attracted our attention to the emerging role of APC/Cdh1 in genomic integrity, cellular differentiation and human diseases. This review will aim to summarize the recently expanded understanding of APC/Cdh1 in regulating biological function and how its dysfunction may lead to diseases.

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Figures

Figure 1
Figure 1
Mission for APC/Cdh1 in mitosis and G1 progression. In mitosis, APC/Cdh1 coordinates with APC/Cdc20 to orchestrate the sequential destruction of mitotic proteins triggering onset of anaphase and further regulating cytokinesis as well as mitotic exit. In coordination with the SCF complex, APC/Cdh1 controls several critical events in G1, including G1/G0 regulation, G1/S phase transition and initiation of DNA replication.
Figure 2
Figure 2
A critical role of APC/Cdh1 in genomic integrity. (A) Emerging functions of Cdh1 in the regulation of the DNA damage checkpoint response. Precise Rad17 proteolysis ensures Rad17 function in both activation and deactivation of the DNA damage checkpoint. In fibroblasts, Rad17 is stabilized following UV to play its role in checkpoint activation. Rad17 destruction by APC/Cdh1 at a later time results in dissociation of claspin, a bridge connecting Chk1 and ATR, from the checkpoint complex. Thereby, degradation of Rad17 after completion of the DNA damage response contributes to termination of checkpoint signaling. (B) Deregulation of APC/Cdh1 may lead to chromosome aberrations and genomic instability. Genotoxic stress leads to unscheduled activation of Cdh1 resulting in abrogated G2/M progression, spindle body assembly and chromatid segregation. Deregulated Cdh1 induces centrosome aberrations and impaired cytokinesis. Moreover, disrupted Cdh1 function leads to genetic instability by inducing DNA rereplication. In addition, APC/Cdh1 is involved in DNA repair through regulating the dNTP pool.
Figure 3
Figure 3
An important role of APC/Cdh1 in coordination between cell division and cellular differentiation. APC/Cdh1 regulates differentiation by controling cell cycle withdrawal and onset of synthesis of certain differentiation related license factors via removal of pertinent transcriptional inhibitors. Stabilization of p27 and p21 via Skp2 degradation by APC/Cdh1, which in turn downregulates CDK2, CDK4 as well as CDK1 activities, is thought to be crucial for cell cycle withdrawal. Destruction of some transcriptional inhibitors such as Id1, 2 and 4 is critical to induce terminal differentiation in certain tissues. Examples include cardiomyocyte generation, myogenesis, neuronal morphogenesis, lens differentiation and bud formation.
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