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.

The Role of Aneuploidy in Cancer Evolution

“…Owing to its interaction with AURKBcontaining chromosomal passenger complex, SGO1 mislocalization impairs error correction. This supports the notion that cohesion defects might cause CIN through stabilization of k-MT attachment errors (Kleyman et al 2014;Tanno et al 2015).…”

Complete loss of STAG2 expression is an indicator of good prognosis in patients with bladder cancer

“…It is likely that the absence of STAG2 expression is not the independent cause of aneuploidy. Furthermore, STAG2 is also essential in the efficient correction of kinetochore-microtubule attachment errors [21], and it is a transcriptional co-activator of NF-kB, suggesting STAG2 could contribute to the control of the expression of genes involved in cell cycle progression [22]. These studies have revealed the reasons for the loss of STAG2 expression driving the process of cancer initiation; however, the mechanism of action of STAG2 loss and its influence on good prognosis need to be clarified in the future.…”

Non-Random Mis-Segregation of Human Chromosomes

“…Moreover, cohesion defects are known to promote chromosome lagging as shown by studies depleting the Retinoblastoma protein pRb (Manning et al, 2010) or STAG2, a component of the cohesin complex (Kleyman et al, 2014). To test whether cohesion fatigue was occurring during the 8-hour nocodazole treatment used herein, and whether this preferentially affected chromosomes 1 and 2, cells were treated with nocodazole for 8 hours followed by release into the proteasome inhibitor MG132 to delay anaphase but allow chromosome-MT attachments to form.…”