Phosphorylation of Chromosome Core Components May Serve as Axis Marks for the Status of Chromosomal Events during Mammalian Meiosis
Open Access
- 9 February 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 8 (2), e1002485
- https://doi.org/10.1371/journal.pgen.1002485
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. Meiosis is a specialized cell division to generate haploid sperm and eggs. For accurate segregation of homologous chromosomes during the first meiotic division, chromosome synapsis and recombination should be properly established between them during the prophase I stage. Chromosome synapsis and recombination proceed in the context of the meiotic chromosome axis. While studies using knockout mouse models have revealed that chromosome axis components play roles in multiple chromosomal events during mammalian meiosis, it remains to be elucidated how they contribute to the processes. Here, we show that many mammalian meiotic chromosome axis proteins are phosphorylated in a spatially and temporally distinct manner during the prophase I stage. Especially, phosphorylation of HORMAD1 and SMC3 was observed preferentially in chromosomal regions where synapsis has not occurred. Moreover, phosphorylation of HORMAD1 and HORMAD2 was reduced in mutant testicular cells that were defective in recombination initiation or chromosome axis organization. Additionally, the mutant spermatocytes failed to correctly distribute checkpoint proteins that coordinate chromosome synapsis with gene expression and meiotic progression. Thus, it is suggested that phosphorylation of chromosome axis proteins serves as integrative axis marks for the status of events that take place on meiotic chromosomes.This publication has 61 references indexed in Scilit:
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