Human Wapl Is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase

Gandhi, R., Gillespie, P. J., Hirano, T. (December 2006) Human Wapl Is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase. Curr Biol, 16 (24). pp. 2406-17. ISSN 0960-9822 (Print)

URL: https://www.ncbi.nlm.nih.gov/pubmed/17112726
DOI: 10.1016/j.cub.2006.10.061

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: DNA
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromatid
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > cohesin
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > cohesin complex
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > metaphase
CSHL Authors:
Communities: CSHL labs > Hirano lab
Depositing User: CSHL Librarian
Date: 19 December 2006
Date Deposited: 19 Dec 2011 14:56
Last Modified: 13 Apr 2018 16:21
PMCID: PMC1850625
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22793

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