WAPL-Mediated Removal of Cohesin Protects against Segregation Errors and Aneuploidy

Abstract

The classical X shape of mitotic human chromosomes is the consequence of two distinct waves of cohesin removal. First, during prophase and prometaphase, the bulk of cohesin is driven from chromosome arms by the cohesin antagonist WAPL. This arm-specific cohesin removal is referred to as the prophase pathway [1-4]. The subsequent cleavage of the remaining centromeric cohesin by Separase is known to be the trigger for anaphase onset [5-7]. Remarkably the biological purpose of the prophase pathway is unknown. We find that this pathway is essential for two key mitotic processes. First, it is important to focus Aurora B at centromeres to allow efficient correction of erroneous microtubule-kinetochore attachments. In addition, it is required to facilitate the timely decatenation of sister chromatids. As a consequence, WAPL-depleted cells undergo anaphase with segregation errors, including both lagging chromosomes and catenanes, resulting in micronuclei and DNA damage. Stable WAPL depletion arrests cells in a p53-dependent manner but causes p53-deficient cells to become highly aneuploid. Our data show that the WAPL-dependent prophase pathway is essential for proper chromosome segregation and is crucial to maintain genomic integrity.

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

“…S1A), but there was a 40% decrease in the amount of Aurora B kinase localized to centromeres. Instead, Aurora B kinase localized along the length of chromosome arms, similar to the localization observed when Bub1, Sgo1 or Wapl are disrupted (Ricke et al, 2012;Rivera et al, 2012;Haarhuis et al, 2013). This change in localization of Aurora B kinase was mimicked by the distribution of INCENP (Fig.…”

The Opposing Actions of Arabidopsis CHROMOSOME TRANSMISSION FIDELITY7 and WINGS APART-LIKE1 and 2 Differ in Mitotic and Meiotic Cells

“…Likewise, alterations in spindle morphology and microtubule attachment are common in meiocytes of both wapl1-1 wapl2 and wapl1-1 wapl ctf7 plants. WAPL depletion can result in the distribution of the chromosome passenger complex along mitotic chromosome arms and its depletion at the centromeres, resulting in altered microtubule attachment and erroneous microtubule-kinetochore attachments and errors in mitotic chromosome segregation (van der Waal et al, 2012;Haarhuis et al, 2013). The erroneous microtubule-kinetochore attachment and alterations in chromosome condensation and decatenation observed in wapl1-1 wapl ctf7 plants are consistent with possible alterations in centromeric cohesin structure.…”

“…While we cannot rule out these possibilities, we suggest that mitosis in leaf cells is likely normal and that the apparent aneuploidy is due to a general increase in genomic instability in the mutants and not to chromosome segregation alterations during mitosis. It is well established that cohesin complexes play an important role in DNA repair (Dorsett and Merkenschlager, 2013) and that inactivation of WAPL results in genomic instability (Haarhuis et al, 2013). Loss of WPL1 activity in yeast has been linked to interallelic recombination, chromosomal amplification, and aneuploidy at rates 17-fold higher than wild-type colonies (Covo et al, 2014a(Covo et al, , 2014b.…”

Multiple Determinants and Consequences of Cohesion Fatigue in Mammalian Cells

“…We depleted Wapl via RNAi, treated the SMC1-GFP cells with ProTAME and examined cells with clear SMC1-GFP signals on metaphase chromosomes, namely those with efficient Wapl depletion (Supplementary figure 2F). Normally, Cohesin released into the cytoplasm by the prophase pathway obscures the residual chromosome-bound population, but Wapl depletion results in strong retention of chromosome Cohesin (Gandhi et al, 2006;Haarhuis et al, 2013;Haarhuis et al, 2017;Tedeschi et al, 2013).…”