Molecular Insights into Meiotic Chromosome Synapsis from Single Molecule Analysis
In humans, defects in meiotic chromosome synapsis and segregation results in aneuploidy leading to miscarriages and genetic disorders. Aneuploidy occurs with much higher probability for the female counterpart, and increases dramatically with age. An evolutionarily conserved meiosis-specific proteinaceous structure, the synaptonemal complex (SC), is required for normal synapsis of meiotic chromosomes. However, very little is known about the biochemical properties of SC components or the mechanisms underlying their roles in meiotic chromosome synapsis and recombination. Structural and functional analysis of Saccharomyces cerevisiae Hop1, a key structural component of SC, has begun to reveal important insights into its function in the synapsis of meiotic chromosomes. Toward this end, we showed that Hop1 is a structure-specific DNA-binding protein, displays higher binding affinity for G-quadruplex DNA and the Holliday junction, and causes structural distortion of the latter at the core of the junction. Using atomic force microscopy and magnetic tweezers techniques, we discovered that Hop1 exhibits the ability to bridge non-contiguous DNA segments into intramolecular stem-loop structures in which the DNA segments are fully synapsed within the filamentous protein stems. Additional evidence suggested that Hop1 folds DNA into rigid protein-DNA filaments and higher-order nucleoprotein structures. Importantly, Hop1 promotes robust intra- and intermolecular synapsis between double-stranded DNA molecules, suggesting that juxtaposition of DNA sequences may assist in strand exchange between homologs by recombination-associated proteins. Furthermore, evidence from in vitro and in vivo studies disclosed the existence of G-quadruplex and i-motif structures at meiosis-specific recombination hot spots. Taken together, these studies support the notion that understanding of meiotic chromosome synapsis and recombination must consider protein binding interactions in conjunction with DNA structural motifs at meiosis-specific recombination hotspots.
