MFPL: What is the synaptonemal complex?

…and why should we care?

First observed in 1956 as a protein ribbon that connects parental chromosomes during a stage in gametogenesis in nearly all organisms capable of sex, the synaptonemal complex has remained stubbornly enigmatic for the last 60 years. Despite a list of its molecular components, the questions of how exactly the chromosomes are linked and what its biological role is remained open.

The Research Groups of Andrea Pichler (MPI, Freiburg) and Franz Klein (MFPL, Vienna) have just published a discovery in Molecular Cell that illuminates the mechanism of synapsis. They provide strong evidence that SUMO (Small Ubiquitin-like MOdifier), a small protein, known to be conjugated to target proteins, can form chains. Such chains seem to represent a medium to which structural components of the parental chromosomes can bind, likening the synaptonemal complex therefore to a zipper with SUMO chains being part of the teeth. Polymerization of the synaptonemal complex is driven by production of SUMO chains, which is governed, as the Pichler lab elegantly shows, by an unusual modification within the SUMO machinery itself. Together the two labs present the analysis of a mutation in the SUMO pathway, the biochemical defect of which lies exclusively in SUMO-chain formation. In vivo, the same mutation leads to complete elimination of the synaptonemal complex.

The attachment of SUMO takes place in three sequential enzyme-dependent steps. Until now, it was assumed that the third step of the reaction – during which SUMO is ligated to its substrate and that is catalyzed by several different enzymes – defines the target for the reaction. Step two on the other hand – during which SUMO is transferred to a conjugating enzyme – was assumed to be unimportant for regulation. In yeast, step two is carried out by a single SUMO conjugating enzyme called Ubc9. Now, Helene Klug from the Pichler group proved this assumption wrong by showing that Ubc9 loses catalytic activity if SUMOylated. She showed that instead Ubc9 becomes an assistant to unmodified Ubc9 to make chains of SUMO molecules. Using mass spectrometry the researchers could show for the first time that SUMO-SUMO conjugates, and therefore SUMO chains, exist in vivo in yeast.

Not being able to form chains, however, did not have detectable consequences for yeast cells, until they attempted meiosis, where the synaptonemal complex must link the parental homologous chromosomes. Martin Xaver from the Klein group showed that no synaptonemal complex formed in the SUMO-chain defective mutants, and SUMO failed to accumulate along the chromosome axes, suggesting that in wild-type cells SUMO chains are required to physically link the chromosome axes.

The researchers are eager to do the next step: For the first time they can ask for the biological consequences of removing only the physical links between the chromosome axes. It will also be fascinating to see in which form this system is conserved in humans. Understanding this critical phase in gametogenesis is important to understand fertility and its decline associated with maternal age.

Original publication in Molecular Cell
Klug H, Xaver M, Chaugule VK, Koidl S, Mittler G, Klein F, Pichler A. Ubc9 Sumoylation Controls SUMO Chain Formation and Meiotic Synapsis in Saccharomyces cerevisiae. Mol Cell. 2013 Apr 30.

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