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| Milestone 23
Making and breaking bonds between sisters
Timing is everything in cell division. For instance, after a dividing cell has duplicated its chromosomes, it takes great care not to separate the copies until it is sure that duplication was completed successfully and that the copies have all been lined up correctly. Otherwise, each newly formed daughter cell will be saddled with an incorrect complement of genetic material. Chromosomes are duplicated in S phase, but the two copies (sister chromatids) are kept together until much later, being pulled apart at the metaphase-to-anaphase transition during mitosis. Yet, as Frank Uhlmann from the Imperial Cancer Research Fund in London says, "From the chromosome's viewpoint, it seems a paradoxical task, to first be tightly linked to its sister copy, but then to let it go into the opposite daughter cell." How does this come about? One of the first pieces of the story was discovered four years ago, with two studies in Cell reporting components of a complex that keeps sister chromatids stuck together. Kim Nasmyth and colleagues started by reasoning that, if there is a protein-based glue that keeps sister chromatids together for much of the cell cycle, then that glue might be destroyed at the start of anaphase to allow chromatids to separate. The anaphase-promoting complex (APC) is involved in the scheduled destruction of proteins that control the cell cycle, and Nasmyth and colleagues wondered whether the APC might also have a role in destroying the sister-chromatid glue. Their screen for mutant yeasts in which sister chromatids can separate in the absence of APC function identified several proteins - three of which, Smc1, Smc3 and Scc1, are essential for cohesion. Scc1 proved particularly interesting, for it dissociates from chromosomes at the start of anaphase. The authors christened these proteins 'cohesins'. A different approach led Doug Koshland and co-workers to the same protein. They looked for yeast mutants that showed defective mitosis, and fished out a protein that they called Mcd1. Again, they found that this protein (Scc1/Mcd1) is needed for sister-chromatid cohesion; and it is linked to chromosomes through Smc1. A year later, Tatsuya Hirano and colleagues' discovery of Xenopus counterparts of Smc1, Smc3 and Scc1, described in Genes and Development, showed that these results are also relevant to vertebrates - albeit with some differences. These discoveries paint a broad-brush picture of how chromatids are kept together. But how, then, are sisters separated when the time is right? We know that, in yeast, a protein called Esp1 (dubbed 'separase') is somehow needed, and that this protein is blocked by Pds1 ('securin') for much of the cell cycle. At the start of anaphase, Pds1 is destroyed by a process involving the APC, and this sparks chromatid separation. Writing in Nature in 1999, Nasmyth and colleagues showed that Esp1 is required to destroy Scc1 at the onset of anaphase (see diagram). They discovered that Scc1 is cleaved at the start of anaphase - but not when Esp1 is mutated. They also generated an uncleavable Scc1, and found that cells expressing this protein could not separate sister chromatids.
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