Practice question

Persistent cohesion between sister chromatids depends on cohesin, tetrameric ring of Smc1, Smc3 ATPases, kleisin Scc1/Rad21 and stromalin SA1/2 subunits embracing replicated DNA strands. During prophase most arm cohesin dissociates via Wapl-dependent opening after Plk1 and Aurora B phosphorylation of SA2, while centromeric pool protected by Shugoshin recruiting PP2A-B56 counteracting phosphorylation remains for biorientation. Final dissolution at anaphase onset requires proteolytic cleavage. Separase, 230 kDa cysteine protease of CD clan, executes this. Kept inactive by dual mechanisms including pseudosubstrate binding of securin chaperone covering conserved active site and phosphorylation by CDK1-Cyclin B1 promoting cyclin B interaction, separase activates only after APC/C-Cdc20 polyubiquitinates securin and cyclin B for proteasomal destruction. Freed separase recognizes conserved separase cleavage motif Glu-X-X-Arg in Scc1 and cleaves after Arg arginine 172 and 450 in human Rad21, opening ring structure and allowing spontaneous dissociation. Cleaved cohesin fragments removed, permitting microtubule pulling forces to drive disjunction. Separase also cleaves itself, cohesin-independent roles in FEAR activation and centriole disengagement. 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.