Dynamic control of sister chromatid cohesion: How is DNA association of cohesin regulated by Wapl and acetylation

DNA is a macromolecule present in each cell, which acts as the genetic information carrier in all organisms (from bacteria to humans). This genetic information is passed from parents to their offspring and decides their biological characteristics. During cell proliferation, all of the DNA is precisely duplicated to form identical 'sister DNAs'.

Subsequently, the sister DNAs must be accurately separated and equally distributed into the two newborn daughter cells. If anything goes wrong during this process, cells will encounter catastrophic consequences, such as cell death or malfunction. This will lead to cancer and other diseases, for example, developmental disorders.

To prevent premature separation and ensure the faithful passing of genetic information from parent cells to daughter cells, the replicated sister DNAs must be held together through a mechanism called sister chromatid cohesion. Only when the cells are fully prepared and the sister DNAs are ready to separate is the sister chromatid cohesion removed, to permit the movement of the sister DNAs to opposite poles of the cell.

Sister chromatid cohesion is achieved through a protein complex called cohesin, which consists of three protein subunits. Besides sister chromatid cohesion, cohesin also plays important roles in compacting DNA, regulating gene expression, and repairing damaged DNA. Though it is responsible for multiple functions on DNA, cohesin actually has a very simple mode to interact with DNA.

The three subunits of cohesin form a ring structure and DNA is entrapped within this ring. To enable cohesin to carry out its functions, the ring can open and close, allowing the DNA fiber to get in or out of the ring. Precise regulation of the opening and closing of the ring is fundamental for cohesin's versatile functions.

Defects in this regulation compromise cohesin's function, leading in humans to cancer and inherited developmental disorders (such as Cornelia de Lange syndrome and Roberts syndrome).

A key protein for regulating the opening of the cohesin ring is called Wapl. Wapl is crucial for the removal of sister chromatid cohesion when sister DNAs are ready to separate. Compromising Wapl function causes delayed intellectual development during childhood.

Although Wapl was discovered about twenty years ago, our knowledge of the molecular mechanism of Wapl-dependent cohesin ring opening has progressed very little. The key challenge for studying this process is caused by the transient interaction of Wapl with cohesin, which poses a barrier to understanding how Wapl physically interacts with cohesin. In this study, we will used advanced in vivo crosslink techniques to reveal which part of cohesin is bound by Wapl, revealing how Wapl opens the cohesin ring.

This approach combined with biochemical analysis will unveil the molecular mechanism through which Wapl triggers disassociation of cohesin from DNA. Insight into this fundamental process will improve our understanding of how DNA segregation occurs in cell division, and how it can go wrong to cause cancer or failures in the developmental programme leading to cohesin-related diseases.