New Solutions to Old Problems: Molecular Mechanisms of Meiotic Crossover Control

Abstract

Meiotic crossovers are important for proper chromosome segregation to form viable haploid gametes from diploid precursors. Crossovers too near each other, or too near the centromere, block proper segregation and may lead to birth defects and infertility. Crossovers are spaced far apart by ‘interference’, first observed in 1915, and are kept away from the centromere by ‘pericentric repression’, observed in 1932. Crossover interference in Schizosaccharomyces pombe stems from DNA double-strand break (DSB) interference at hotspots, which form clusters through DSB hotspot-determinant proteins; both types of interference are regulated by Tel1 protein kinase. Pericentric repression stems from DSB inhibition due to absence of a key activator, the meiosis-specific sister chromatid cohesin subunit Rec11 in S. pombe and its homolog STAG3 in mammals, by complex circuitry now elucidated. During scientific investigations, the explanation of remarkably interesting phenomena must often await development of new methods or accrual of new observations that in retrospect can lead to lucid answers to the initial problem. A case in point is the control of genetic recombination during meiosis, which leads to crossovers between chromosomes critical for production of healthy offspring. Crossovers must be properly placed along meiotic chromosomes for their accurate segregation. Here, we review observations on two aspects of meiotic crossover control – crossover interference and repression of crossovers near centromeres, both observed more than 85 years ago. Only recently have relatively simple molecular mechanisms for these phenomena become clear through advances in both methods and understanding the molecular basis of meiotic recombination.