title: STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments.
abstract: Mutations in the STAG2 gene are present in ∼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 a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the 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 mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) 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.
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA Norris Cotton Cancer Center, Lebanon, NH 03766, USA.
authors: Marianna
authors: M
authors: Kleyman
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA Norris Cotton Cancer Center, Lebanon, NH 03766, USA.
authors: Lilian
authors: L
authors: Kabeche
authors: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA Norris Cotton Cancer Center, Lebanon, NH 03766, USA duane.a.compton@dartmouth.edu.
authors: Duane A
authors: DA
authors: Compton
mesh_terms: D000782:Aneuploidy; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D043171:Chromosomal Instability; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; C508565:STAG2 protein, human; D000097722:Cohesins
keywords: Aneuploidy; Chromosomal instability; Kinetochore; Merotely; Mitosis; STAG2