The Fidelity of Synaptonemal Complex Assembly Is Regulated by a Signaling Mechanism that Controls Early Meiotic Progression

Abstract

Proper chromosome segregation during meiosis requires the assembly of the synaptonemal complex (SC) between homologous chromosomes. However, the SC structure itself is indifferent to homology, and poorly understood mechanisms that depend on conserved HORMA-domain proteins prevent ectopic SC assembly. Although HORMA-domain proteins are thought to regulate SC assembly as intrinsic components of meiotic chromosomes, here we uncover a key role for nuclear soluble HORMA-domain protein HTP-1 in the quality control of SC assembly. We show that a mutant form of HTP-1 impaired in chromosome loading provides functionality of an HTP-1-dependent checkpoint that delays exit from homology search-competent stages until all homolog pairs are linked by the SC. Bypassing of this regulatory mechanism results in premature meiotic progression and licensing of homology-independent SC assembly. These findings identify nuclear soluble HTP-1 as a regulator of early meiotic progression, suggesting parallels with the mode of action of Mad2 in the spindle assembly checkpoint.

The Chromosome Axis Mediates Feedback Control of CHK-2 to Ensure Crossover Formation in C. elegans

“…Our evidence demonstrates that the meiotic checkpoint is fully functional even in the absence of PC activity and that CHK-2 feedback regulation is rather a nucleus-wide response. This directly refutes the recent proposal that HIM-8 is required for feedback in early meiotic prophase (Silva et al, 2014). This confusion arose because the previous study did not directly monitor CHK-2 activity, but instead the recruitment of PLK-2 to PCs, which requires not only CHK-2 activity but also the zinc finger proteins, specifically HIM-8 under conditions where the ZIMs do not remain phosphorylated.…”

Meiosis

“…Although the mechanisms by which these two proteins promote homolog pairing are not well understood, HTP-1 has been proposed to participate in two checkpoint-like mechanisms: the first makes initiation of SC assembly contingent on successful homology recognition, while the second prolongs the homology search process until homolog interactions are stabilized by SC loading (Couteau and Zetka, 2005: PMID 16291647; Martinez-Perez and Villeneuve, 2005: PMID 16291646; Silva et al, 2014: PMID 25455309). A mutant form of HTP-1 that fails to associate with axial elements still supports the delayed exit from early prophase triggered by synapsis defects, suggesting that nuclear soluble HTP-1 may participate in the quality control of SC assembly (Silva et al, 2014: PMID 25455309). An important difference between htp-1 and him-3 null mutants is that SC assembly is dramatically reduced in him-3 mutants, whereas lack of HTP-1 results in high levels of SC assembly between non-homologous chromosomes.…”

“…This delay requires HTP-1: htp-1; syp-2 double mutants have no zygotene arrest, leading to the proposal that HTP-1 participates in the generation of an inhibitory signal that blocks exit from zygotene until the SC is installed between all homologous pairs (Martinez-Perez and Villeneuve, 2005: PMID 16291646). This inhibitory signal appears to involve a soluble pool of HTP-1, since a mutant version of HTP-1 that fails to associate with axial elements still supports zygotene arrest in SC-deficient mutants (Silva et al, 2014: PMID 25455309). SC assembly appears to directly antagonize the inhibitory signal that blocks early meiotic progression, as improper SC assembly between sister chromatids in syp-3(me42) mutants results in normal meiotic progression (Smolikov et al, 2007b: PMID 17565948).…”

Meiotic recombination and the crossover assurance checkpoint in Caenorhabditis elegans

“…The “patchy” aggregates of SUN-1 and ZYG-12 seen at the nuclear envelope in transition zone nuclei persist longer, as does phosphorylation of SUN-1 at several N-terminal serine/threonine residues [80,81,102,103], in diverse mutants with synapsis or crossover defects. These nuclear envelope markers likely reflect the presence of the Polo-like kinase PLK-2 at pairing centers, which is also prolonged under these conditions [89,104]. The disappearance of DSB-1 and DSB-2 from meiotic chromosomes shows a similar temporal dependence on the ability to establish crossover intermediates on all chromosomes [18,32].…”