Wings apart-like protein homolog (WAPL) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the ''WAPAL''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. WAPL is a key regulator of the

Cohesin Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 ( SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA re ...

complex which mediates

sister chromatid cohesion A sister is a woman or a girl who shares one or more parents with another individual; a female sibling. The male counterpart is a brother. Although the term typically refers to a family, familial relationship, it is sometimes used endearingly to r ...

, homologous recombination and DNA looping. Cohesin is formed of

SMC3 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 ...

, SMC1,

RAD21 Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the ''RAD21'' gene. ''RAD21'' (also known as ''Mcd1'', ''Scc1'', ''KIAA0078'', ''NXP1'', ''HR21''), an essential gene, encodes a DNA double-strand break (D ...

and either SA1 or SA2. 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 Sister chromatid cohesion protein PDS5 homolog A is a protein that in humans is encoded by the ''PDS5A'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." mea ...

PDS5B 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 loo ...

and releases cohesin from DNA by opening the interface between SMC3 and RAD21.

Interphase

Cohesin loading begins in telophase and is mediated by

NIPBL Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the ''NIPBL'' gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozy ...

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 Shugoshin 1 or Shugoshin-like 1, is a protein that in humans is encoded by the ''SGO1'' gene. Model organisms Model organisms have been used in the study of SGOL1 function. A conditional knockout mouse line, called ''Sgol1tm1a(EUCOMM)Wtsi'' h ...

and

PP2A Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in ...

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. 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. It is not known how WAPL regulates the process of ATP binding.

References

{{gene-10-stub