CRL4 regulates recombination and synaptonemal complex aggregation in the Caenorhabditis elegans germline

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.

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“…These errors are probably due partly to a deregulation of modular cullin RING ligase 4 (CRL4) whose meiotic targets have not been characterised. The effect of rubylation (also known as neddylation) and CRL4 on synapsis and CO formation has also been described in Caenorhabditis elegans 30,31 .…”

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“…Disruption of CUL4 expression leads to a similar meiotic phenotype to axr1 mutants indicating that the axr1 meiotic phenotype might reflect perturbed CUl4 rubylation mediated by RBX1 which acts as both an E3 in the rubylation cascade and as part of SCF and cullin ring ligase 4 (CRL) ubiquitin E3 complexes ( Jahns et al, 2014 ). In C. elegans , mutants of the CRL4 components CUL4 and DDB-1 also display aberrant synapsis with SYP-1, the ZYP1 equivalent, failing to polymerize normally, forming large polycomplexes ( Brockway et al, 2014 ; Alleva et al, 2019 ). Interestingly, RBX1 mutants showed no defects in synapsis ( Alleva et al, 2019 ).…”

“…In C. elegans , mutants of the CRL4 components CUL4 and DDB-1 also display aberrant synapsis with SYP-1, the ZYP1 equivalent, failing to polymerize normally, forming large polycomplexes ( Brockway et al, 2014 ; Alleva et al, 2019 ). Interestingly, RBX1 mutants showed no defects in synapsis ( Alleva et al, 2019 ). However, the role of CUL4 in SC formation does not appear to be universal as cul4A knockout mutants synapse fully in mouse spermatocytes ( Kopanja et al, 2011 ; Yin et al, 2011 ).…”