BACKGROUND: The linkage between duplicated chromosomes (sister chromatids) is 
established during S phase by the action of cohesin, a multisubunit complex 
conserved from yeast to humans. Most cohesin dissociates from chromosome arms 
when the cell enters mitotic prophase, leading to the formation of metaphase 
chromosomes with two cytologically discernible chromatids. This process is known 
as sister-chromatid resolution. Although two mitotic kinases have been 
implicated in this process, it remains unknown exactly how the cohesin-mediated 
linkage is destabilized at a mechanistic level.
RESULTS: The wings apart-like (Wapl) protein was originally identified as a gene 
product that potentially regulates heterochromatin organization in Drosophila 
melanogaster. We show that the human ortholog of Wapl is a cohesin-binding 
protein that facilitates cohesin's timely release from chromosome arms during 
prophase. Depletion of Wapl from HeLa cells causes transient accumulation of 
prometaphase-like cells with chromosomes that display poorly resolved sister 
chromatids with a high level of cohesin. Reduction of cohesin relieves the 
Wapl-depletion phenotype, and depletion of Wapl rescues premature sister 
separation observed in Sgo1-depleted or Esco2-depleted cells. Conversely, 
overexpression of Wapl causes premature separation of sister chromatids. Wapl 
physically associates with cohesin in HeLa-cell nuclear extracts. Remarkably, in 
vitro reconstitution experiments demonstrate that Wapl forms a stoichiometric, 
ternary complex with two regulatory subunits of cohesin, implicating its 
noncatalytic function in inactivating cohesin's ability to interact with 
chromatin.
CONCLUSIONS: Wapl is a new regulator of sister chromatid resolution and promotes 
release of cohesin from chromosomes by directly interacting with its regulatory 
subunits.