Wapl is an essential regulator of chromatin structure and chromosome segregation

Abstract

Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin-DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin-DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.

“Breaking Up Is Hard to Do”: The Formation and Resolution of Sister Chromatid Intertwines

“…In Xenopus the dosage of cohesin complexes on chromosomes influences the final shape of the condensed chromosome, probably by antagonizing the activity of the condensin II complex [79] (metazoans have multiple condensin type complexes -reviewed by Hirano [66]). It has now being shown in mammalian cells that deletion of the cohesin regulator Wapl causes premature chromosome condensation in interphase and extensive chromosome bridging in anaphase [80]. Wapl is normally required for the pre-anaphase release of DNA bound cohesin complexes so its deletion leads to the stabilization of cohesin on DNA [81,82].…”

Two independent modes of chromatin organization revealed by cohesin removal

“…Since the turnover of chromosome-bound cohesin is ~20 minutes 23,24 , constant loading is required for its presence on DNA. We achieved efficient deletion of Nipbl in non-dividing hepatocytes by using a liver-specific, tamoxifen-inducible Cre driver (Fig.…”

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

“…However, for reasons that are not yet understood, ctf7 plants can be obtained at low frequencies; the plants are dwarf, exhibit severe developmental abnormalities, and are completely sterile (Bolaños-Villegas et al, 2013). Inactivation of WAPL results in lethality in Drosophila melanogaster, nematodes (Caenorhabditis elegans), and animal cells (Vernì et al, 2000;Kamath et al, 2003;Tedeschi et al, 2013); however the growth of wpl1/rad61 yeast mutants is indistinguishable from the wild type (Bennett et al, 2001). Similar to the situation in yeast, WAPL inactivation in Arabidopsis has very little effect on growth and development.…”

“…This led to the suggestion that Pds5 and Ctf7/ Eco1 promote condensation through a common WAPL-mediated mechanism regulated by Rad51 (Tong and Skibbens, 2015). Mouse cells depleted for Wapl contain partially condensed chromosomes with regions of hypercondensed heterochromatin (Tedeschi et al, 2013). It is has been suggested that this could be due in part to a failure to remove catenates during late prophase.…”