The Function And Mechanism Research Of UV-induced CUEDC2Degradation In G1/S Arrest

DNA damage induced by various genotoxic stresses can jeopardize genomicintegrity. UV light is the most pervasive environmental DNA-damaging agent, andaccumμlating evidence indicates that overexposure to UV light woμld increase therisk of skin cancer development. To maintain genomic stability, DNA damageresponse triggers cell cycle arrest, especially G1arrest, which allows time for DNArepair and prevents aberrant replication of damaged DNA[1]. Timely down-regμlationof cell cycle promoters and rapid accumμlation of cell cycle inhibitors are critical forDNA damage-induced G1arrest. Earlier studies have indicated that the DNAdamage-induced G1arrest is mainly achieved by p53activation and the subsequentp21（Cyclin-dependent kinase inhibitor1） accumμlation. However, p21is degradedfollowing UV irradiation and does not play a role in this process[2]. Thus, themolecμlar mechanism underlying UV-induced G1arrest is not fμlly understood.Understanding the regμlation of UV-induced G1arrest will μltimately help to developnovel strategies for skin cancer prevention and therapy.CUE-domain-containing protein2(CUEDC2) plays critical roles in severalimportant signaling pathways[3-7]. The anaphase-promoting complex or cyclosome(APC/C), a mμltisubunit E3ubiquitin ligase, is an important regμlator of proteindegradation during the cell cycle. Activation of APC/C requires the association ofeither cell division cycle protein20(Cdc20) or Cdc20homolog1(Cdh1), two relatedcoactivators that recognize specific substrates containing the destruction box (D-box)or the lysine(K)-glutamic acid(E)-asparagine(N)(KEN) motif[8-10]. Cdc20functionsin early mitosis, whereas Cdh1has crucial functions in both late mitosis and G1bytargeting mμltiple cell cycle regμlators, such as Cyclin A, Cyclin B1, and S-phasekinase-associated protein2(Skp2) for degradation[8,9,11-14]. Our recent work hasdemonstrated that CUEDC2is phosphorylated by CDK1and promotes spindlecheckpoint inactivation through releasing APC/CCdc20from checkpoint inhibitionduring mitosis[5].In the current study, we show that CUEDC2exists in nonphosphorylated form in G1phase, and inhibits APC/CCdh1activity through binding to Cdh1in aKEN-box–dependent manner[15]. Upon UV treatment, CUEDC2undergoesubiquitination–dependent degradation. Destruction of CUEDC2releases APC/CCdh1activity, resμlting in Cyclin A destruction, CDK2inactivation, and G1arrest.Collectively, our resμlts identify CUEDC2as a regμlator of APC/CCdh1and implicateits regμlated degradation as an important mechanism for UV-induced G1arrest.The superfamily of tripartite motif-containing (TRIM) proteins is a group ofRING-type E3ubiquitin ligases[16]. Many TRIM proteins are crucial for manyaspects of resistance to pathogens, and several are known to be required for therestriction of infection by lentiviruses[17]. Recently, some members of TRIM proteinshad been suggested to involve in tumor development and progression[18,19]. One ofthe TRIM proteins, TRIM21has been shown to regμlate the stability of severalsubstrates including cell cycle regμlators, although its role in tumor development isnot clear[20]. In this study, analyses of mass spectrometry indicate that CUEDC2bindsto TRIM21and regμlates CUEDC2protein degradation via ubiquitin-proteasomepathway upon UV irradiation. We further show that CUEDC2are highly expressed inhuman skin cancers. Importantly, we found that the level of TRIM21is dramaticallydecreased and CUEDC2becomes resistant to UV-induced degradation in skin cancercells. These resμlts identify the E3ligase TRIM21as a specific regμlator of CUEDC2degradation and suggest that deregμlation of CUEDC2expression may contribute toskin cancer development.