Polo-like kinase-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop.

摘要

The majority of DNA in animal cells is stored in structures called chromosomes. Most cells contain two sets of chromosomes, one inherited from the mother and one from the father. Sperm and egg cells, however, contain only a single set of chromosomes. A specialized type of cell division called meiosis generates these cells. During meiosis, the chromosomes in a cell replicate to produce a cell that contains four copies of each chromosome. The equivalent chromosomes from the mother and the father are initially kept close together by a zipper-like structure called the synaptonemal complex. This allows the chromosomes to exchange segments of DNA, before the cell divides twice in successive rounds to produce four cells, each containing one set of chromosomes. Severing both of the DNA strands that make up a DNA molecule forms what is known as a double-strand break. To exchange DNA segments with another chromosome, double-strand breaks that form in the DNA of one chromosome are repaired in a process known as crossover formation. Only a subset of the double-strand breaks are designated to be repaired by crossover formation, but at least one crossover needs to form between each chromosome pair. This generates diversity and ensures that the chromosomes separate correctly at the first cell division. Since the synaptonemal complex holds equivalent chromosomes close together it ensures that at least some of the breaks are repaired by crossover formation. Nadarajan et al. have now investigated how a chemical modification called phosphorylation affects how the synaptonemal complex behaves in the roundworm Caenorhabditis elegans. A combination of genetic and cell-based approaches revealed that enzymes called polo-like kinases phosphorylate one of the proteins – called SYP-4 – that makes up the synaptonemal complex. This phosphorylation occurs after double-strand break sites have been designated to become crossovers. The synaptonemal complex is normally a dynamic structure, with the proteins that it consists of being continuously replaced. However, Nadarajan et al. found that phosphorylating SYP-4 made the synaptonemal complex less dynamic than it had previously been, which prevented further double-strand breaks from forming. Polo-like kinases are found in many organisms, from yeast to humans. Further work is now needed to investigate whether polo-like kinases phosphorylate the synaptonemal complex – and hence prevent the continuous formation of double-strand breaks – in animals such as mice and humans. This is important because failing to shut down the formation of double-strand breaks can result in cancer, infertility, miscarriages and birth defects in humans.