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#chromosome separation

4 public questions tagged with this topic.

Cell Division

What happens during anaphase II of meiosis?

Meiosis consists of two divisions following single S phase, with meiosis II equationally separating sisters after reductional meiosis I segregated homologs. Cells exit meiosis I entering interkinesis without replication, centrosomes duplicate, chromosomes recondense, and spindle reforms often orthogonal to first division axis. At metaphase II plate, sister chromatids align with kinetochores bioriented to opposite poles similar to mitosis, achieved despite haploid chromosome number. Protection of centromeric cohesion established in meiosis I by Shugoshin SGO2 bound to PP2A phosphatase that dephosphorylates Rec8 cohesin preventing separase cleavage is now removed as SGO2 degrades from centromeres. Upon APC/C-Cdc20 activation at anaphase II, securin degraded, separase active cleaves remaining centromeric Rec8, dissolving cohesion. Sister chromatids, now genetically non-identical due to crossing over in prophase I exchanging non-sister segments, separate toward opposite poles driven by kinetochore microtubule depolymerization and spindle elongation, generating four haploid daughter cells essential for sexual reproduction and complementation after fertilization. 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.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 21: Meiosis II Sister Chromatids.

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Cell Cycle Regulation

Which protein is degraded by APC to trigger chromosome separation?

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.

Ref: Uhlmann et al., Nature 1999, Separase Cohesin Cleavage. Alberts 7th ed., Chapter 17, Securin.

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Cell Cycle Regulation

Separase is activated when:

Separase activation integrates checkpoint satisfaction with physical separation of chromatids. Newly synthesized separase folds with assistance of securin chaperone, which inserts its own reactive site loop into catalytic pocket, blocking proteolysis and ensuring proper localization to nucleus. Parallel inhibition involves CDK1-Cyclin B1 binding phosphorylating separase at Ser1126 creating docking site for cyclin B. At metaphase, with all kinetochores amphitelically attached, spindle assembly checkpoint silencing allows APC/C-Cdc20 E3 ligase to become active. APC/C-Cdc20 recognizes KEN-box and D-box degron sequences on securin, catalyzing assembly of K11 and K48 linked polyubiquitin chains. Polyubiquitinated securin targeted to 26S proteasome with half-life decreasing from hours to under ten minutes. Simultaneously cyclin B degradation removes CDK1-mediated inhibition. Removal of securin exposes catalytic dyad histidine and cysteine residues allowing cleavage of cohesin kleisin Scc1/Rad21 at EXXR motifs. Some separase autocleavage yields C-terminal fragment with retained activity. Securin therefore acts both as inhibitor and as folding assistant, while APC/C functions as trigger linking ubiquitination to proteolysis-driven anaphase initiation. 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.

Ref: Peters, Control of Securin Degradation by APC/C-Cdc20, Nat Rev Mol Cell Biol; Hornig et al., Securin-Separase Complex Structure.

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