Fundamental cell cycle kinases collaborate to ensure timely destruction of the synaptonemal complex during meiosis

Abstract

The synaptonemal complex (SC) is a proteinaceous macromolecular assembly that forms during meiotic prophase I and mediates adhesion of paired homologous chromosomes along their entire lengths. Although prompt disassembly of the SC during exit from prophase I is a landmark event of meiosis, the underlying mechanism regulating SC destruction has remained elusive. Here, we show that DDK (Dbf4-dependent Cdc7 kinase) is central to SC destruction. Upon exit from prophase I, Dbf4, the regulatory subunit of DDK, directly associates with and is phosphorylated by the Polo-like kinase Cdc5. In parallel, upregulated CDK1 activity also targets Dbf4. An enhanced Dbf4-Cdc5 interaction pronounced phosphorylation of Dbf4 and accelerated SC destruction, while reduced/abolished Dbf4 phosphorylation hampered destruction of SC proteins. SC destruction relieved meiotic inhibition of the ubiquitous recombinase Rad51, suggesting that the mitotic recombination machinery is reactivated following prophase I exit to repair any persisting meiotic DNA double-strand breaks. Taken together, we propose that the concerted action of DDK, Polo-like kinase, and CDK1 promotes efficient SC destruction at the end of prophase I to ensure faithful inheritance of the genome.

Regulation of Hed1 and Rad54 binding during maturation of the meiosis‐specific presynaptic complex

“…Interestingly, Rad51 plays a late role in meiotic prophase by repairing residual DSBs after disassembly of the synaptonemal complex (Argunhan et al, 2017;Prugar et al, 2017). Reactivation of Rad51 coincides with inactivation of Mek1, and as a result, Rad54 phosphorylation and Hed1 phosphorylation are lost, and Hed1 is degraded (Callender et al, 2016;Argunhan et al, 2017;Prugar et al, 2017). These observations suggest that reversion of the meiotic-like presynaptic complex to a mitotic-like presynaptic complex may require the active removal and proteolytic degradation of Hed1.…”

“…Our data suggest that the mechanism underlying this transition is kinetic competition between Rad54 and Hed1 for binding interactions with Rad51 ( Fig 7B). Interestingly, Rad51 plays a late role in meiotic prophase by repairing residual DSBs after disassembly of the synaptonemal complex (Argunhan et al, 2017;Prugar et al, 2017). So, the first of these two proteins, either Rad54 or Hed1, to engage the presynaptic complex will dictate its functional identity as "mitotic-like" (i.e., with strand exchange driven by Rad51) or "meiotic-like" (i.e., with strand exchange driven by Dmc1), and once the functional identity of the presynaptic complex is established, then this identity may be maintained until the complexes complete strand invasion or until the complexes are actively dismantled.…”

“…In support of this model, we find that Rad54 and Hed1 binding interactions are mutually exclusive, and once established, these binding interactions are effectively irreversible over the time scales that might be relevant to meiotic progression ( Fig 7B). Reactivation of Rad51 coincides with inactivation of Mek1, and as a result, Rad54 phosphorylation and Hed1 phosphorylation are lost, and Hed1 is degraded (Callender et al, 2016;Argunhan et al, 2017;Prugar et al, 2017). Interestingly, Rad51 plays a late role in meiotic prophase by repairing residual DSBs after disassembly of the synaptonemal complex (Argunhan et al, 2017;Prugar et al, 2017).…”

“…So, the first of these two proteins, either Rad54 or Hed1, to engage the presynaptic complex will dictate its functional identity as "mitotic-like" (i.e., with strand exchange driven by Rad51) or "meiotic-like" (i.e., with strand exchange driven by Dmc1), and once the functional identity of the presynaptic complex is established, then this identity may be maintained until the complexes complete strand invasion or until the complexes are actively dismantled. Interestingly, Rad51 plays a late role in meiotic prophase by repairing residual DSBs after disassembly of the synaptonemal complex (Argunhan et al, 2017;Prugar et al, 2017). Reactivation of Rad51 coincides with inactivation of Mek1, and as a result, Rad54 phosphorylation and Hed1 phosphorylation are lost, and Hed1 is degraded (Callender et al, 2016;Argunhan et al, 2017;Prugar et al, 2017).…”

Slx5p‐Slx8p Promotes Accurate Chromosome Segregation by Mediating the Degradation of Synaptonemal Complex Components during Meiosis

“…The expression of Cdc5p triggers an untimely disassembly of the SC and irregular resolution of recombination intermediates . Cdc5p could collaborate with CDK1 to hyperphosphorylate Dbf4p, the regulatory subunit of Dbf4p‐dependent Cdc7p kinase (DDK), and hyperphosphorylated DDK greatly accelerates SC destruction . However, the substrates of Cdc5p, Dbf4p, and Ipl1p, as well as the precise mechanism underlying their triggering of SC disassembly, remain unknown.…”