Third, cohesion is removed in anaphase I only from chromosome arms and not from the regions near the centromeres, where the kinetochores are located. The loss of arm cohesion triggers homolog separation at the onset of anaphase I. This process depends on APC/C activation, which leads to securin destruction, separase activation, and cohesin cleavage along the arms (see Figure 17–38).
Cohesins near the centromeres are protected from separase in meiosis I by a kinetochore-associated protein called shugoshin (from the Japanese word for “guardian spirit”). Shugoshin acts by recruiting a protein phosphatase that removes phosphates from centromeric cohesins. Cohesin phosphorylation is normally required for separase to cleave cohesin; thus, removal of this phosphorylation near the centromere prevents cohesin cleavage. Sister-chromatid pairs therefore remain linked through meiosis I, allowing their correct bi-orientation on the spindle in meiosis II. Shugoshin is inactivated after meiosis I. At the onset of anaphase II, APC/C activation triggers centromeric cohesin cleavage and sisterchromatid separation—much as it does in mitosis. Following anaphase II, nuclear envelopes form around the chromosomes to produce four haploid nuclei, after which cytokinesis and other differentiation processes lead to the production of haploid gametes.
Crossing-over has two distinct functions in meiosis: it helps hold homologs together so that they are properly segregated to the two daughter nuclei produced by meiosis I, and it contributes to the genetic diversification of the gametes that are eventually produced. As might be expected, therefore, crossing-over is highly regulated: the number and location of double-strand breaks along each chromosome is controlled, as is the likelihood that a break will be converted into a crossover. On average, the result of this regulation is that each pair of human homologs is linked by about two or three crossovers (Figure 17–59).
Although the double-strand breaks that occur in meiosis I can be located almost anywhere along the chromosome, they are not distributed uniformly: they cluster at “hot spots,” where the DNA is accessible, and occur only rarely in “cold spots,” such as the heterochromatin regions around centromeres and telomeres.
Figure 17–59 Crossovers between homologs in the human testis. In these immunofluorescence micrographs, antibodies have been used to stain the synaptonemal complexes (red), the centromeres (blue), and the sites of crossing-over (green). note that all of the bivalents have at least one crossover and none have more than four. (modified from a. Lynn et al., Science 296:2222–2225, 2002. With permission from aaas.)
At least two kinds of regulation influence the location and number of crossovers that form, neither of which is well understood. Both operate before the synaptonemal complex assembles. One ensures that at least one crossover forms between the members of each homolog pair, as is necessary for normal homolog segregation in meiosis I. In the other, called crossover interference, the presence of one crossover event inhibits another from forming close by, perhaps by locally depleting proteins required for converting a double-strand DNA break into a stable crossover.