Ensuring faithful mitosis through STAG2 function

Type Thesis

Rate 0.0 /5

Details

Files

Reviews

Download

Summary

Mutations in the STAG2 gene are present in approximately 20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss of function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are hallmarks of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay normal mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyper-stabilization of kMT attachments. STAG2-deficient cells mislocalize Bub1 kinase and the chromosome passenger complex including Aurora B kinase. Phosphorylation activity of both Bub1 and Aurora B is also compromised in STAG2 knockdown cells. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule destabilizing enzymes MCAK and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis.