Wapl Controls the Dynamic Association of Cohesin with Chromatin

Abstract

Cohesin establishes sister-chromatid cohesion from S phase until mitosis or meiosis. To allow chromosome segregation, cohesion has to be dissolved. In vertebrate cells, this process is mediated in part by the protease separase, which destroys a small amount of cohesin, but most cohesin is removed from chromosomes without proteolysis. How this is achieved is poorly understood. Here, we show that the interaction between cohesin and chromatin is controlled by Wapl, a protein implicated in heterochromatin formation and tumorigenesis. Wapl is associated with cohesin throughout the cell cycle, and its depletion blocks cohesin dissociation from chromosomes during the early stages of mitosis and prevents the resolution of sister chromatids until anaphase, which occurs after a delay. Wapl depletion also increases the residence time of cohesin on chromatin in interphase. Our data indicate that Wapl is required to unlock cohesin from a particular state in which it is stably bound to chromatin.

Functional links between Drosophila Nipped-B and cohesin in somatic and meiotic cells

“…This reduced transmission is very sensitive to changes in the dosage of genes involved in chromosome segregation (Dobie et al 2001). For example, heterozygous wings-apart-like (wapl) mutations, which decrease mitotic chromatid separation by reducing prophase removal of cohesin from chromosome arms, decrease J21A transmission in female meiosis (Dobie et al 2001;Gandhi et al 2006;Kueng et al 2006;Verni et al 2000). Females heterozygous for the parental chromosome in which the Nipped-B 407 and Nipped-B 292.1 mutations were induced (Rollins et al 1999) transmitted J21A at a frequency of 0.24 (348 of 1,441; Table 2).…”

Shugoshin regulates cohesion by driving relocalization of PP2A in Xenopus extracts

“…This population is essential in preventing precocious separation of the sister chromatids and allowing proper chromosome alignment (Vass et al 2003;Vagnarelli et al 2004;. The dissociation of cohesin in prophase requires Polo and Aurora B kinases as well as a number of additional factors that include Wapl Sumara et al 2002;Hauf et al 2005;Gandhi et al 2006;Kueng et al 2006). At the onset of anaphase, cleavage of Scc1/Rad21 by separase drives dissociation of the remaining cohesin and sister chromatid separation ensues (Hauf et al 2001).…”

DNA entry, exit and second DNA capture by cohesin: insights from biochemical experiments

“…Using its flexible middle domain, Scc1 also serves as a docking platform for the HEAT repeat auxiliary proteins Pds5 and Scc2 [26–29]. Scc2, with its stable binding partner Scc4, promotes cohesin loading [30] whereas Pds5, with its substoichiometric binding partner Wapl, dissociates cohesin from chromatin [31–33]. …”

“…This recruitment depends on cohesin’s ATPase and the Scc2-Scc4 cohesin loader [30]. At the same time, cohesin is susceptible to chromatin releasing activity mediated by Pds5-Wapl [31,32]. Thus, cohesin displays dynamic chromosomal association through the balancing acts of these auxiliary proteins.…”