Practice question

Preservation of sister chromatid cohesion until all chromosomes correctly bioriented relies on anaphase inhibitor securin, known as Pds1 in yeast and PTTG1 pituitary tumor transforming gene in mammals. Synthesized during S and G2, securin binds stoichiometric quantities of separase protease through insertion of reactive loop into separase active site, acting as pseudosubstrate and competitive inhibitor. Beyond inhibition, securin serves as chaperone promoting proper folding of separase, its accumulation in nucleus and stability. As long as securin remains associated, separase cannot cleave cohesin subunit Scc1, preventing premature sister separation. At anaphase onset, checkpoint satisfied APC/C-Cdc20 ubiquitin ligase recognizes KEN and D-box degrons on securin, assembling K11/K48 polyubiquitin chains targeting it for rapid proteolysis with half-life dropping to minutes. Degradation frees catalytic histidine-cysteine dyad of separase which then cleaves Rad21 at conserved glutamate-arginine motifs, opening cohesin ring allowing disjunction. Excess securin overexpression observed in pituitary tumors causes metaphase arrest and aneuploidy, while securin deletion still viable due to compensatory CDK1 phosphorylation inhibition of separase. 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.