Accurate segregation of chromosomes during meiosis requires that they pair, synapse, and undergo crossover recombination with their homologs. Although genetic studies over the last few decades have identified a list of components that are essential for these processes, it remains largely unknown how protein machines work together to orchestrate chromosome dynamics.
We are addressing these long-standing questions by combining biochemical and structural analysis using purified components, with the ability to examine meiosis in the context of highly tractable C. elegans germline.
Molecular architecture of the chromosome axis
Early in meiosis, chromosomes are dramatically reorganized into arrays of chromatin loops tethered to a proteinaceous axis, and this is essential for all major meiotic events, including homolog pairing, synapsis and crossover recombination. The chromosome axis also provides a key interface for checkpoint signaling that ensures crossover formation on each homolog pair.
One major focus of our work is the structure and function of chromosome axes. The axis is composed of meiotic cohesins and additional meiosis-specific components, such as HORMA domain proteins. We have demonstrated that meiotic HORMA domain proteins (HIM-3, HTP-1, HTP-2, and HTP-3 in C. elegans) form hierarchical assemblies through binding of their HORMA domains to cognate peptide motifs within their partners (Kim, Rosenberg et al., 2014).
HORMA domain protein assembly in C. elegans
This work has revealed a conserved mode of interactions among meiotic HORMA domain proteins and provided a foundation to investigate how the chromosome axis controls chromosome dynamics. We are currently investigating how the axis interfaces the chromatin and controls meiotic recombination, how it provides a platform for synaptonemal complex assembly, and how it monitors the status of synapsis and crossover formation to mediate checkpoint signaling.
Signaling Cascades in meiotic chromosome dynamics
Key aspects of chromosome dynamics in meiosis, as in mitosis, are controlled by phosphorylation-dependent regulation. The CHK-2 kinase is a master regulator of meiosis in C. elegans. Its activity is required for homolog pairing and synapsis and also for DNA double-strand break formation that initiates meiotic recombination. However, how it drives and coordinates these pathways to ensure crossover formation remains largely unknown.
We found that CHK-2 promotes pairing and synapsis by phosphorylating a family of zinc finger proteins (HIM-8, ZIM-1, ZIM-2, and ZIM-3) that bind to specialized regions on each chromosome known as pairing centers, priming their recruitment of the Polo-like kinase PLK-2. We have also established that CHK-2 is a molecular target of feedback regulation that delays cell cycle progression in response to lack of crossovers. This feedback circuit is mediated by interactions among a network of HORMA domain proteins within the chromosome axis (Kim et al., 2015).
Control of meiotic chromosome dynamics by CHK-2 and PLK-2
We continue to delineate the signaling cascades by major cell cycle kinases and establish the conserved regulatory mechanisms that orchestrate meiotic chromosome dynamics. Our work will ultimately shed light into how organisms faithfully transmit genetic information from one generation to the next.