Abstract:SUMMARY
Crossover (CO) recombination creates a physical connection between homologs that promotes their proper segregation at meiosis I (MI). Failure to realize an obligate CO causes homologs to attach independently to the MI spindle and separate randomly, leading to nondisjunction. However, mechanisms that determine whether homolog pairs have received crossovers remain mysterious. We describe a surveillance system in C. elegans that monitors recombination intermediates and couples their formation to meiotic p… Show more
“…Consistent with our model, the central region of the SC remains dynamic in later stages of meiosis in syp-4 phosphodead mutants (this study) and in meiotic recombination defective mutants (Machovina et al, 2016; Pattabiraman et al, 2017). Moreover, the observation that the SC persists in a more dynamic state during pachytene in spo-11 mutant animals (Machovina et al, 2016; Pattabiraman et al, 2017), despite the lack of programmed meiotic DSB formation in this mutant, rules out the possibility that the elevated DSB levels observed in syp-4 phosphodead mutants cause the prolonged dynamic state of the SC.10.7554/eLife.23437.024Figure 7.Model for how PLK-1/2-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop.In wild type, PLK-1/2-dependent phosphorylation of SYP-4 at the S269 site occurs in response to CO designation. This phosphorylation switches the central region of the SC from a more dynamic (pink) to a less dynamic state (blue) during pachytene, inhibiting additional DSB formation on the homologous chromosomes.…”
The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans. We found that SYP-4 is phosphorylated dependent on Polo-like kinases PLK-1/2. SYP-4 phosphorylation depends on DSB formation and crossover designation, is required for stabilizing the SC in pachytene by switching the central region of the SC from a more dynamic to a less dynamic state, and negatively regulates DSB formation. We propose a model in which Polo-like kinases recognize crossover designation and phosphorylate SYP-4 thereby stabilizing the SC and making chromosomes less permissive for further DSB formation.DOI:
http://dx.doi.org/10.7554/eLife.23437.001
“…Consistent with our model, the central region of the SC remains dynamic in later stages of meiosis in syp-4 phosphodead mutants (this study) and in meiotic recombination defective mutants (Machovina et al, 2016; Pattabiraman et al, 2017). Moreover, the observation that the SC persists in a more dynamic state during pachytene in spo-11 mutant animals (Machovina et al, 2016; Pattabiraman et al, 2017), despite the lack of programmed meiotic DSB formation in this mutant, rules out the possibility that the elevated DSB levels observed in syp-4 phosphodead mutants cause the prolonged dynamic state of the SC.10.7554/eLife.23437.024Figure 7.Model for how PLK-1/2-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop.In wild type, PLK-1/2-dependent phosphorylation of SYP-4 at the S269 site occurs in response to CO designation. This phosphorylation switches the central region of the SC from a more dynamic (pink) to a less dynamic state (blue) during pachytene, inhibiting additional DSB formation on the homologous chromosomes.…”
The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans. We found that SYP-4 is phosphorylated dependent on Polo-like kinases PLK-1/2. SYP-4 phosphorylation depends on DSB formation and crossover designation, is required for stabilizing the SC in pachytene by switching the central region of the SC from a more dynamic to a less dynamic state, and negatively regulates DSB formation. We propose a model in which Polo-like kinases recognize crossover designation and phosphorylate SYP-4 thereby stabilizing the SC and making chromosomes less permissive for further DSB formation.DOI:
http://dx.doi.org/10.7554/eLife.23437.001
“…elegans . Our findings contribute to a growing body of evidence that the SC is a much more dynamic structure than is suggested by its highly-ordered appearance in EM images[32–35]. We show that the SC incorporates new subunits and switches from a more dynamic to a more stable state during progression from the early pachytene to late pachytene stage.…”
Section: Introductionsupporting
confidence: 62%
“…The model proposed here is distinct in several ways from the model recently proposed by Machinova and colleagues [32]. Machinova et al .…”
During meiotic prophase, a structure called the synaptonemal complex (SC) assembles at the interface between aligned pairs of homologous chromosomes, and crossover recombination events occur between their DNA molecules. Here we investigate the inter-relationships between these two hallmark features of the meiotic program in the nematode C. elegans, revealing dynamic properties of the SC that are modulated by recombination. We demonstrate that the SC incorporates new subunits and switches from a more highly dynamic/labile state to a more stable state as germ cells progress through the pachytene stage of meiotic prophase. We further show that the more dynamic state of the SC is prolonged in mutants where meiotic recombination is impaired. Moreover, in meiotic mutants where recombination intermediates are present in limiting numbers, SC central region subunits become preferentially stabilized on the subset of chromosome pairs that harbor a site where pro-crossover factors COSA-1 and MutSγ are concentrated. Polo-like kinase PLK-2 becomes preferentially localized to the SCs of chromosome pairs harboring recombination sites prior to the enrichment of SC central region proteins on such chromosomes, and PLK-2 is required for this enrichment to occur. Further, late pachytene nuclei in a plk-2 mutant exhibit the more highly dynamic SC state. Together our data demonstrate that crossover recombination events elicit chromosome-autonomous stabilizing effects on the SC and implicate PLK-2 in this process. We discuss how this recombination-triggered modulation of SC state might contribute to regulatory mechanisms that operate during meiosis to ensure the formation of crossovers while at the same time limiting their numbers.
“…In addition, COs are maintained, despite variation in the number of interhomolog interactions, by altering the number of NCOs via CO homeostasis. Absence of designated CO sites for each homolog pair delays meiotic progression in C. elegans, suggesting a surveillance mechanism to ensure CO designation (Rosu et al, 2013; Stamper et al, 2013; Woglar et al, 2013; Machovina et al, 2016). In this way, cells can compensate for disruption of early steps of CO formation.…”
Summary
Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate failure to ensure COs in juvenile male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and/or alternative complexes, which can act upon precursors to generate noncrossovers (NCOs) at the expense of COs. We propose that some designated CO sites fail to mature efficiently in juveniles owing to inappropriate activity of these alternative repair pathways, leading to chromosome mis-segregation. We also find lower MutLγ focus density in juvenile human spermatocytes, suggesting that weaker CO maturation efficiency may explain why younger men have higher risk of fathering children with Down syndrome.
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