Practice question

SCF complex forms prototypical cullin-RING ubiquitin ligase governing G1/S and S-phase progression, distinct from mitotic APC/C. Architecture comprises scaffold Cullin1, adaptor Skp1, RING finger Rbx1 recruiting E2 ubiquitin conjugating enzyme, and interchangeable F-box protein providing substrate specificity through WD40 or leucine-rich repeats. Activity regulated by substrate phosphorylation creating phosphodegron that interacts with F-box. During late G1, Cdk2-Cyclin E phosphorylates cyclin-dependent kinase inhibitor p27 Kip1 at Thr187, Sic1 ortholog in yeast at multiple CDK sites and p21 at Ser130, allowing recognition by F-box Skp2 with cofactor Cks1 and subsequent Lys48 polyubiquitination and proteasomal degradation. Removal lifts inhibition on CDK2-Cyclin E and CDK2-Cyclin A permitting origin firing. Similarly, Cdc6 phosphorylated for nuclear export and SCF-mediated clearance, E2F1 turned over after DNA replication. Unlike APC/C which targets D-box substrates during mitosis after activation by Cdc20/Cdh1, SCF depends on prior kinase marking, linking CDK activity and growth signals to degradation. Tumor suppressor Fbw7 component targets Cyclin E, Myc, Notch; mutations accumulate oncogenic substrates contributing to cancers. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.