Abstract
To maintain the integrity of the genome, meiotic DNA double strand breaks (DSBs) need to form by the meiosis-specific nuclease Spo11 and be repaired by homologous recombination. One class of products formed by recombination are crossovers, which are required for proper chromosome segregation in the first meiotic division. The synaptonemal complex (SC) is a protein structure that connects homologous chromosomes during meiotic prophase I. The proper assembly of the SC is important for recombination, crossover formation, and the subsequent chromosome segregation. Here we identify the components of Cullin RING E3 ubiquitin ligase 4 (CRL4) that play a role in SC assembly in Caenorhabditis elegans. Mutants of the CRL4 complex (cul-4, ddb-1, and gad-1) show defects in SC assembly manifested in the formation of polycomplexes (PCs), impaired progression of meiotic recombination, and reduction in crossover numbers. PCs that are formed in cul-4 mutants lack the mobile properties of wild type SC, but are likely not a direct target of ubiquitination. In C. elegans, SC assembly does not require recombination and there is no evidence that PC formation is regulated by recombination as well. However, in one cul-4 mutant PC formation is dependent upon early meiotic recombination, indicating that proper assembly of the SC can be diminished by recombination in some scenarios. Lastly, our studies suggest that CUL-4 deregulation leads to transposition of the Tc3 transposable element, and defects in formation of SPO-11-mediated DSBs. Our studies highlight previously unknown functions of CRL4 in C. elegans meiosis and show that CUL-4 likely plays multiple roles in meiosis that are essential for maintaining genome integrity.
Highlights
Meiosis is a specialized cellular division essential for sexually reproducing metazoans
The germlines of nematodes (Caenorhabditis elegans) that lack protein components of the Cullin 4 E3 Ubiquitin ligase complex (CRL4), have defects in the formation of the synaptonemal complex (SC) that can be due to misfolding of SC proteins and their aggregation
Cullin RING E3 ubiquitin ligase 4 (CRL4) appears to be involved in other germline functions that directly affect chromosome stability (DNA damage repair and transposition), indicating that CRL4 has a central function in the formation of functional sperm and egg cells
Summary
Meiosis is a specialized cellular division essential for sexually reproducing metazoans. Meiosis proceeds by two cellular divisions: the first separates homologous chromosomes and the second separates sister chromatids. In Caenorhabditis elegans, homologous chromosomes pair, synapse, and proceed through meiotic recombination (reviewed in: [3]). In sexually reproducing model organisms, DSB formation and repair require specific components of the SC that are part of the chromosome axis (reviewed in: [4]). SC assembly is not always dependent upon DSB formation and recombination initiation; some species do not require DSB formation or recombination for synapsis (e.g. Drosophila; [5] and C. elegans; [6]). SC assembly depends on DSB formation/ recombination (e.g. mouse; [7] and S. cerevisiae; [8]). Negative regulation of SC assembly, or prevention of aberrant SC formation, by recombination has not yet been described
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