Practice question

Chromatid cohesion must be maintained until synchronous separation at anaphase, requiring protection against premature cleavage. Securin, also called pituitary tumor transforming gene PTTG, functions as dual inhibitor and chaperone of separase. Securin sequence contains D-box and KEN motifs for APC/C recognition and binds separase HEAT repeats, occluding catalytic triad. Accumulation during S and G2 concentrates at centromeres. At metaphase, APC/C-Cdc20 polyubiquitinates securin, triggering rapid proteasomal degradation within five to ten minutes, concentration dropping precipitously. Simultaneously cyclin B destruction inactivates CDK1 that also phosphorylates separase inhibitory sites, fully unleashing protease. Liberated separase translocates to chromosomes and cleaves Rad21/Scc1 kleisin at conserved EXXR motifs after glutamate, generating N- and C-terminal fragments unable to maintain ring closure. This opens cohesin, allowing kinetochore microtubules to pull sisters to opposite poles. Expression of non-degradable securin mutant with mutated D-box prevents cohesion loss and arrests cells in metaphase with intact cohesion. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.