| Structural highlights
Function
[WAPL_HUMAN] Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin. Involved in both sister chromatid cohesion during interphase and sister-chromatid resolution during early stages of mitosis. Couples DNA replication to sister chromatid cohesion. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Cohesin, along with positive regulators, establishes sister-chromatid cohesion by forming a ring to circle chromatin. The wings apart-like protein (Wapl) is a key negative regulator of cohesin and forms a complex with precocious dissociation of sisters protein 5 (Pds5) to promote cohesin release from chromatin. Here we report the crystal structure and functional characterization of human Wapl. Wapl contains a flexible, variable N-terminal region (Wapl-N) and a conserved C-terminal domain (Wapl-C) consisting of eight HEAT (Huntingtin, Elongation factor 3, A subunit, and target of rapamycin) repeats. Wapl-C folds into an elongated structure with two lobes. Structure-based mutagenesis maps the functional surface of Wapl-C to two distinct patches (I and II) on the N lobe and a localized patch (III) on the C lobe. Mutating critical patch I residues weaken Wapl binding to cohesin and diminish sister-chromatid resolution and cohesin release from mitotic chromosomes in human cells and Xenopus egg extracts. Surprisingly, patch III on the C lobe does not contribute to Wapl binding to cohesin or its known regulators. Although patch I mutations reduce Wapl binding to intact cohesin, they do not affect Wapl-Pds5 binding to the cohesin subcomplex of sister chromatid cohesion protein 1 (Scc1) and stromal antigen 2 (SA2) in vitro, which is instead mediated by Wapl-N. Thus, Wapl-N forms extensive interactions with Pds5 and Scc1-SA2. Wapl-C interacts with other cohesin subunits and possibly unknown effectors to trigger cohesin release from chromatin.
Structure of the human cohesin inhibitor Wapl.,Ouyang Z, Zheng G, Song J, Borek DM, Otwinowski Z, Brautigam CA, Tomchick DR, Rankin S, Yu H Proc Natl Acad Sci U S A. 2013 Jun 17. PMID:23776203[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Oikawa K, Ohbayashi T, Kiyono T, Nishi H, Isaka K, Umezawa A, Kuroda M, Mukai K. Expression of a novel human gene, human wings apart-like (hWAPL), is associated with cervical carcinogenesis and tumor progression. Cancer Res. 2004 May 15;64(10):3545-9. PMID:15150110 doi:10.1158/0008-5472.CAN-03-3822
- ↑ Kueng S, Hegemann B, Peters BH, Lipp JJ, Schleiffer A, Mechtler K, Peters JM. Wapl controls the dynamic association of cohesin with chromatin. Cell. 2006 Dec 1;127(5):955-67. Epub 2006 Nov 16. PMID:17113138 doi:10.1016/j.cell.2006.09.040
- ↑ Gandhi R, Gillespie PJ, Hirano T. Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase. Curr Biol. 2006 Dec 19;16(24):2406-17. Epub 2006 Nov 16. PMID:17112726 doi:10.1016/j.cub.2006.10.061
- ↑ Shintomi K, Hirano T. Releasing cohesin from chromosome arms in early mitosis: opposing actions of Wapl-Pds5 and Sgo1. Genes Dev. 2009 Sep 15;23(18):2224-36. doi: 10.1101/gad.1844309. Epub 2009 Aug, 20. PMID:19696148 doi:10.1101/gad.1844309
- ↑ Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV. Cohesin acetylation speeds the replication fork. Nature. 2009 Nov 12;462(7270):231-4. PMID:19907496 doi:nature08550
- ↑ Nishiyama T, Ladurner R, Schmitz J, Kreidl E, Schleiffer A, Bhaskara V, Bando M, Shirahige K, Hyman AA, Mechtler K, Peters JM. Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell. 2010 Nov 24;143(5):737-49. doi: 10.1016/j.cell.2010.10.031. PMID:21111234 doi:10.1016/j.cell.2010.10.031
- ↑ Ouyang Z, Zheng G, Song J, Borek DM, Otwinowski Z, Brautigam CA, Tomchick DR, Rankin S, Yu H. Structure of the human cohesin inhibitor Wapl. Proc Natl Acad Sci U S A. 2013 Jun 17. PMID:23776203 doi:10.1073/pnas.1304594110
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