WAPAL

Last updated
WAPL
Crystal Structure of Human WAPL (PDB 4K6J).png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases WAPL , FOE, KIAA0261, WAPAL, WAPL cohesin release factor
External IDs OMIM: 610754 MGI: 2675859 HomoloGene: 41002 GeneCards: WAPL
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_015045
NM_001318328

NM_001004436
NM_001301330

RefSeq (protein)

NP_001305257
NP_055860

NP_001004436
NP_001288259

Location (UCSC) Chr 10: 86.44 – 86.52 Mb Chr 14: 34.4 – 34.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. [5] [6] [7] WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. [8] Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.

Contents

Interphase

Structure of PDS5B (blue), WAPL (green) and IP6 (PDB 5HDT) (Ouyang et al., 2016) Structure of PDS5B (blue), WAPL (green) and IP6 (PDB 5HDT) (Ouyang et al., 2016).png
Structure of PDS5B (blue), WAPL (green) and IP6 (PDB 5HDT) (Ouyang et al., 2016)

Cohesin loading begins in telophase and is mediated by NIPBL and its binding partner MAU2. In G1, WAPL forms a complex with PDS5 and removes cohesin from the DNA but it is reloaded by NIPBL-MAU2. The equilibrium between loading and release give cohesin a DNA residence time of 20 minutes. During DNA replication, a fraction of cohesin is acetylated and binds to Sororin making it resistant to WAPL and able to hold sister chromatids together. This is crucial for the maintenance of sister chromatid cohesion because onse the sister chromatids are separated, cohesion cannot be reestablished.

Prophase pathway

When a cell enters mitosis, Sororin is phosphorylated causing it to dissociate from cohesin meaning WAPL can remove cohesin from the DNA. A complex of SGOL1 and PP2A dephosphorylates cohesin at the centromere protecting it from WAPL-mediated release. Sister chromatid cohesion is therefore maintained at the centromeres where it is required for mitosis but lost on the arms. This removal of cohesin is known as the Prophase Pathway and results in the X-shape sister chromatids observed in chromosome spreads.

Mechanism

WAPL releases cohesin from DNA by opening the SMC3-RAD21 interface thereby allowing DNA to pass out of the ring. [9] Opening of this interface is regulated by ATP-binding by the SMC subunits. This causes the ATPase head domains to dimerise and deforms the coiled coil of SMC3 therefore disrupting the binding of RAD21 to the coiled coil. [10] It is not known how WAPL regulates the process of ATP binding.

Related Research Articles

<span class="mw-page-title-main">Centromere</span> Specialized DNA sequence of a chromosome that links a pair of sister chromatids

The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers attach to the centromere via the kinetochore.

<span class="mw-page-title-main">Meiosis</span> Type of cell division in sexually-reproducing organisms used to produce gametes

Meiosis is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and female will fuse to create a cell with two copies of each chromosome again, the zygote.

<span class="mw-page-title-main">Condensin</span>

Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis. Their subunits were originally identified as major components of mitotic chromosomes assembled in Xenopus egg extracts.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

<span class="mw-page-title-main">Separase</span>

Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.

<span class="mw-page-title-main">Chromomere</span>

A chromomere, also known as an idiomere, is one of the serially aligned beads or granules of a eukaryotic chromosome, resulting from local coiling of a continuous DNA thread. Chromeres are regions of chromatin that have been compacted through localized contraction. In areas of chromatin with the absence of transcription, condensing of DNA and protein complexes will result in the formation of chromomeres. It is visible on a chromosome during the prophase of meiosis and mitosis. Giant banded (Polytene) chromosomes resulting from the replication of the chromosomes and the synapsis of homologs without cell division is a process called endomitosis. These chromosomes consist of more than 1000 copies of the same chromatid that are aligned and produce alternating dark and light bands when stained. The dark bands are the chromomere.

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

<span class="mw-page-title-main">SMC1A</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">RAD21</span> Protein-coding gene in the species Homo sapiens

Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.

<span class="mw-page-title-main">SMC3</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.

<span class="mw-page-title-main">STAG2</span> Protein-coding gene in the species Homo sapiens

Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">SGOL1</span>

Shugoshin-like 1 is a protein that in humans is encoded by the SGOL1 gene.

<span class="mw-page-title-main">PDS5B</span>

Sister chromatid cohesion protein PDS5 homolog B(PDS5B) is a protein that in humans is encoded by the PDS5B gene. It is a regulatory subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. The core cohesin complex is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. PDS5 associates with WAPL to stimulate the release of cohesin from DNA but during DNA replication PDS5 promotes acetylation of SMC3 by ESCO1 and ESCO2.

Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.

<span class="mw-page-title-main">PDS5A</span>

Sister chromatid cohesion protein PDS5 homolog A is a protein that in humans is encoded by the PDS5A gene.

<span class="mw-page-title-main">REC8</span>

Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">SMC1B</span>

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000062650 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000041408 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, et al. (October 1996). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Research. 3 (5): 321–9, 341–54. doi: 10.1093/dnares/3.5.321 . PMID   9039502.
  6. Gandhi R, Gillespie PJ, Hirano T (December 2006). "Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase". Current Biology. 16 (24): 2406–17. doi:10.1016/j.cub.2006.10.061. PMC   1850625 . PMID   17112726.
  7. "Entrez Gene: WAPAL wings apart-like homolog (Drosophila)".
  8. Yatskevich S, Rhodes J, Nasmyth K (December 2019). "Organization of Chromosomal DNA by SMC Complexes". Annual Review of Genetics. 53: 445–482. doi: 10.1146/annurev-genet-112618-043633 . PMID   31577909.
  9. Beckouët F, Srinivasan M, Roig MB, Chan KL, Scheinost JC, Batty P, et al. (February 2016). "Releasing Activity Disengages Cohesin's Smc3/Scc1 Interface in a Process Blocked by Acetylation". Molecular Cell. 61 (4): 563–574. doi:10.1016/j.molcel.2016.01.026. PMC   4769318 . PMID   26895425.
  10. Muir KW, Li Y, Weis F, Panne D (March 2020). "The structure of the cohesin ATPase elucidates the mechanism of SMC-kleisin ring opening". Nature Structural & Molecular Biology. 27 (3): 233–239. doi:10.1038/s41594-020-0379-7. PMC   7100847 . PMID   32066964.