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Abstract
Meiotic recombination and chromosome synapsis between homologous chromosomes are essential for proper chromosome segregation at the first meiotic division. While recombination and synapsis, as well as checkpoints that monitor these two events, take place in the context of a prophase I-specific axial chromosome structure, it remains unclear how chromosome axis components contribute to these processes. We show here that many protein components of the meiotic chromosome axis, including SYCP2, SYCP3, HORMAD1, HORMAD2, SMC3, STAG3, and REC8, become post-translationally modified by phosphorylation during the prophase I stage. We found that HORMAD1 and SMC3 are phosphorylated at a consensus site for the ATM/ATR checkpoint kinase and that the phosphorylated forms of HORMAD1 and SMC3 localize preferentially to unsynapsed chromosomal regions where synapsis has not yet occurred, but not to synapsed or desynapsed regions. We investigated the genetic requirements for the phosphorylation events and revealed that the phosphorylation levels of HORMAD1, HORMAD2, and SMC3 are dramatically reduced in the absence of initiation of meiotic recombination, whereas BRCA1 and SYCP3 are required for normal levels of phosphorylation of HORMAD1 and HORMAD2, but not of SMC3. Interestingly, reduced HORMAD1 and HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes, suggesting that these post-translational events contribute to the regulation of the synapsis surveillance system. We propose that modifications of chromosome axis components serve as signals that facilitate chromosomal events including recombination, checkpoint control, transcription, and synapsis regulation.
Highlights
Meiosis is a special type of cell division that gives rise to haploid gametes required for sexual reproduction
Phosphatase-sensitive protein bands were detected for SYCP2, SYCP3, STAG3, REC8, HORMAD1 and HORMAD2 (Figure 1A, black and gray arrowheads), whereas no obvious mobility shifts were seen for SMC3 and SMC1b (Figure 1A)
SYCP2 was found to be highly enriched in the insoluble fraction, whereas the other chromosome axis proteins were found in both fractions (Figure 1B)
Summary
Meiosis is a special type of cell division that gives rise to haploid gametes required for sexual reproduction. At the first stage of meiosis, the leptotene stage of prophase I, recombination is initiated between homologous chromosomes (homologs) by programmed DNA double-strand breaks (DSBs) formed by the SPO11 protein [1]. Recombination is, in some organisms including mice, required for synapsis of homologs [2,3]. At the pachytene stage of prophase I, the homologs become fully synapsed by the SCs and repair of a subset of DSBs results in crossover recombination. At the diplotene stage of prophase I, the SCs are disassembled and the homologs undergo desynapsis, attached to each other only at crossover sites. The physical connections between the homologs, called chiasmata, are essential for correct segregation of the homologs at the anaphase stage of meiosis I [6]. Processes that transform the nature of meiotic chromosomes, such as recombination and synapsis, are executed in a coordinated manner during prophase I
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