During meiosis, parental chromosomes are recombined to give genetically related but unique progeny. This basic process is common to all sexually reproducing eukaryotes and is accomplished through DNA double-strand breaks (DSBs) that are repaired by matching DNA strand ends with sequences on intact homologous chromosomes, a sequence of steps collectively called chromosomal crossover formation. In humans, roughly 2-4 crossover events occur per chromosome, giving rise to subtle genetic differences observed between parents and children while also guiding the proper segregation of chromosomes during meiosis to form viable gametes (eggs and sperm in humans) and healthy progeny. The history of research on meiotic recombination is long and rich. First described by the German biologist Oscar Hertwig studying sea urchin eggs in the late 1800’s, it is still a very active area of research.
One observation, made more than 80 years ago about precisely where on chromosomes crossovers happen, has fueled research in Dr. Gerry Smith’s laboratory in the Basic Sciences Division. That observation is that crossover events can occur almost anywhere along each of a chromosome’s arms except for the central region, or centromere. There is good reason to prevent recombination and DSBs near the centromere as the centromere serves a critical function in parceling out chromosomes to daughter cells and defects in chromosome segregation can lead to genetic disorders such as Down syndrome. Furthermore, crossovers near the centromere make chromosomes prone to missegregation. The mystery was this: how do cells protect centromeric regions from meiotic recombination? The answer to the riddle was reported by Smith and his postdoctoral colleague Dr. Mridula Nambiar in Molecular Cell.
To understand how recombination is prevented at centromeres, it is necessary to understand how it occurs at other locations. During DNA replication, proteins necessary for chromosome cohesion and recombination are deposited more or less uniformly along chromosomes. Regions surrounding the centromeres, the pericentromeres, receive cohesin complexes containing a slightly different complement of proteins. Cohesion is required for proper segregation of sister chromatids during mitosis. A protein essential to make DSBs and thus recombination is Spo11, a protein relative of the topoisomerases, enzymes that create transient DSBs to relieve torsional stress. Endonucleolytic degradation of DNA at the meiotic DSBs creates regions of 3’ single-stranded DNA that are used to search for homologous sequences in intact sister chromatids or homologs. Once located, the single-stranded “primer” invades the intact chromosome and uses it as a template to “repair” the broken chromosome, leading to the formation of a chimeric chromosome, part from one parent, part from the other. Prevention of chromosomal crossover events near the centromere, also known as pericentric regions, could occur at one of several steps leading up to DSB formation. To unravel the mystery, the authors used Schizosaccharomyces pombe, or fission yeast, a genetically tractable model organism. By examining the roles of individual protein components of chromosome cohesion and recombination complexes, Smith and Nambiar discovered a dual role for the Swi6 protein, which localizes to the pericentric regions but not to chromosomal arms, that neatly provides the solution to the long-standing question.
In meiosis, meiosis-specific cohesin complexes containing the Rec8 protein are deposited along chromosome arms to form a multi-subunit complex containing either Rec11 along chromosome arms or its close relative Psc3 at pericentromeres. While both complexes are critical for cohesion, they play distinctly different roles in recombination. The unique localization of the Rec8-Pcs3 complex depends on the Swi6 protein, which contains a recognition module called the chromodomain that localizes it to DNA regions enriched in a pericentromere-specific histone modification, H3K9me. Swi6 recruits Rec8-Psc3 to pericentromeres ensuring proper chromosome cohesion, a prerequisite for accurate chromosome segregation, while at the same time preventing Rec11 from localizing there. The Rec11 protein, in concert with several other proteins, activates Spo11, the inducer of DSBs, but Psc3 lacks this activity. The Rec8-Rec11 complex along chromosome arms activates Spo11 leading to recombination, while the Rec8-Pcs3 complex along with Swi6 prevents Spo11 activation at pericentromeres. Mystery solved!
Nambiar M and Smith GR. 2018. Pericentromere-specific cohesin complex prevents meiotic pericentric DNA double-strand breaks and lethal crossovers. Molecular Cell. Aug 16;71(4):540-553.e4
This research was supported by grants from the National Institutes of Health.