APC/C^cdh1 Controls Cell Cycle Entry And Impacts DNADamage During Liver Regeneration

The Ubiquitin-mediated proteolysis is an evolutionarily conserved cellular mechanism and has been implicated in a variety of cellular processes including mitosis,regulation of the immune system,transcriptional control,signal transduction,and development.Ubiquitin ligase complexes controls a variety of cellular processes by targeting different substrates for proteasomal timely degradation.The anaphase-promoting complex or cyclosome(APC/C)function through two related adapter proteins,Cdc20 and Cdh1 family,which contain a conservative WD40 sequence,make the substrate ubiquitination.In the metaphase,Cdc20 binds to APC/C and activates it,destructive securin to facilitate sister-chromatid separation.APC/CCdc20 promote the metaphase-anaphase transition through initiates cyclins degradation and decreases CDK activity.While the other activator,Cdh1,is able to bind to it at the late stage of mitosis and maintain its activity in the subsequent G1 phase,all of which indicates its important role in G1/S transformation.As a conserved player in G0/G1 regulation from yeast to human,the biological relevance of Cdh1 in cell cycle control has been extensively studied in recent years.Although Cdh1 plays a very important role in the cell cycle progression,so far,other celluar functions have not been fully explored.Since Cdh1-deficient mice have embryonic lethality,this limits their functional studies in vivo.Liver is a highly differentiated and metabolic function organ,and liver parenchymal cells rarely divide,partial hepatectomy can make liver cells split quickly.In order to characterize Cdh1 in liver regeneration,we generated a conditional knock-out and partial hepatectomy mouse model.Our data showed that loss of Cdh1 leads to increased and extended S phase progression possibly due to the upregulation of cyclin D1.Moreover,the increased DNA replication resulted in activated DNA damage response.Interestingly,the final liver weight after partial hepatectomy in the Cdh1 depleted mice did not differ from that of the controls,implying that Cdh1 is not required for the competence of hepatocytes to regenerate itself.