We show that multiple, functionally specialized cohesin complexes mediate the establishment and two-step release of sister chromatid cohesion that underlies the production of haploid gametes. In C. elegans, the kleisin subunits REC-8 and COH-3/4 differ between meiotic cohesins and endow them with distinctive properties that specify how cohesins load onto chromosomes and then trigger and release cohesion. Unlike REC-8 cohesin, COH-3/4 cohesin becomes cohesive through a replication-independent mechanism initiated by the DNA double-stranded breaks that induce crossover recombination. Thus, break-induced cohesion also tethers replicated meiotic chromosomes. Later, recombination stimulates separase-independent removal of REC-8 and COH-3/4 cohesins from reciprocal chromosomal territories flanking the crossover site. This region-specific removal likely underlies the two-step separation of homologs and sisters. Unexpectedly, COH-3/4 performs cohesion-independent functions in synaptonemal complex assembly. This new model for cohesin function diverges from that established in yeast but likely applies directly to plants and mammals, which utilize similar meiotic kleisins.
Most plant and animal cells have a pair of each chromosome: one copy is inherited from the father, the other from the mother. When a cell divides, each daughter cell must receive a copy of all of the original cell's genetic information. To this end, the chromosomes are replicated to form so-called ‘sister chromatids’, which are then segregated equally between the two daughter cells.
In contrast, sex cells such as eggs and sperm (also called gametes) have a single copy of each chromosome. When an egg and a sperm fuse to form a single cell (called a zygote), the zygote ends up with a full set of chromosomes. Gametes are formed by two successive rounds of cell division that occur after the chromosomes are replicated. The first round separates the pairs of chromosomes, and the second separates the sister chromatids to produce the gametes, each of which has half the original amount of genetic information.
If something goes awry in the production of gametes, a zygote can end up with the wrong number of chromosomes. Almost one-third of human zygotes inherit an aberrant complement of chromosomes, and many of these zygotes either fail to survive or develop into offspring with birth defects and developmental disorders.
To ensure that gametes receive the correct number of chromosomes, the sister chromatids remain bound together by a ring-shaped protein complex during the first cell division. Previous studies on how this protein complex—called cohesin—tethers the sister chromatids together were conducted on yeast and mammalian cells. Now, Severson and Meyer show that, in a microscopic worm called Caenorhabditis elegans, cohesin functions differently from how it functions in the simpler yeast cells.
Severson and Meyer found that rather than using a single cohesin complex like in yeast, the worms use multiple cohesin complexes that have different versions of one key protein subunit. Changing this single subunit has a major impact on cohesin's function. Consequently, each complex plays a specific role in tethering and then releasing sister chromatids. One of the cohesin complexes is triggered to tether the sister chromatids when the chromosomes replicate. Unexpectedly, another complex only tethers the sisters once breaks occur in the DNA. These breaks allow sister chromatids that are produced from maternally- and paternally-derived chromosomes to cross over and swap genetic material—which increases the genetic diversity of any future offspring. After these genetic swaps occur, the cohesin complexes are then selectively removed by different mechanisms, first to release the pairs of chromosomes and then the sister chromatids.
The findings of Severson and Meyer establish a new model for the mechanisms of chromosome segregation during gamete production. Further studies are now needed to determine the roles and regulation of these protein complexes in other species—including plants and mammals, which use similar cohesin complexes.