Abstract
Proper cell cycle progression is safeguarded by the oscillating activities of cyclin/cyclin-dependent kinase complexes. An important player in the regulation of mitotic cyclins is the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase. Prior to entry into mitosis, the APC/C remains inactive, which allows the accumulation of mitotic regulators. APC/C activation requires binding to either the Cdc20 or Cdh1 adaptor protein, which sequentially bind the APC/C and facilitate targeting of multiple mitotic regulators for proteasomal destruction, including Securin and Cyclin B, to ensure proper chromosome segregation and mitotic exit. Emerging data have indicated that the APC/C, particularly in association with Cdh1, also functions prior to mitotic entry. Specifically, the APC/C-Cdh1 is activated in response to DNA damage in G2 phase cells. These observations are in line with in vitro and in vivo genetic studies, in which cells lacking Cdh1 expression display various defects, including impaired DNA repair and aberrant cell cycle checkpoints. In this review, we summarize the current literature on APC/C regulation in response to DNA damage, the functions of APC/C-Cdh1 activation upon DNA damage, and speculate how APC/C-Cdh1 can control cell fate in the context of persistent DNA damage.
Highlights
Reproduction depends on successful cell division, which is coordinated in the cell cycle
anaphase-promoting complex/cyclosome (APC/C) activation requires binding to either the Cdc20 or Cdh1 adaptor protein, which sequentially bind the anaphase-promoting complex’ (APC)/C and facilitate targeting of multiple mitotic regulators for proteasomal destruction, including Securin and Cyclin B, to ensure proper chromosome segregation and mitotic exit
We summarize the current literature on APC/C regulation in response to DNA damage, the functions of APC/C-Cdh1 activation upon DNA damage, and speculate how APC/C-Cdh1 can control cell fate in the context of persistent DNA damage
Summary
Reproduction depends on successful cell division, which is coordinated in the cell cycle. This second pool presumably becomes active upon DNA damage, due to Cdc14B-mediated dephosphorylation of Cdh and/or down-regulation of CDK activity [42] This model is supported by the observation that USP28 depletion does not lead to general degradation of APC/C-Cdh targets, and the observation that Emi association with the APC/C does not appear to be controlled by DNA damage [38]. Cdh is required to down-regulate components of the replication and mitotic spindle machinery, and APC/C-Cdh activity in G1 phase prevents the accumulation of essential genes for another round of DNA replication In line with this notion, inactivation of mouse Fzr gene (encoding Cdh1) prevented the terminal differentiation of neuronal progenitors and resulted in increased proliferation of neuronal stem cells, and defective neurogenesis [70, 71]. Both G9a and GLP undamaged G cells 2 Emi
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
