title: Controlling the response to DNA damage by the APC/C-Cdh1.
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.
authors.affiliation: Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: H Rudolf
authors.initials: HR
authors.lastname: de Boer
authors.affiliation: Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Guerrero Llobet
authors.affiliation: Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.vugt@umcg.nl.
authors.forename: Marcel A T M
authors.initials: MA
authors.lastname: van Vugt
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases
keywords: Cell cycle; Checkpoint; Cyclosome; DNA damage; E3 ligase