The Meiosis Tango
Where would we be without meiosis and recombination? Nowhere. All sexually produced life would not exist, as sperm and eggs are made through meiosis. When meiosis doesn't work it can lead to infertility, miscarriage, birth defects and developmental disorder.
Meiosis is a type of cell division to reduce the number of chromosomes in a parent cell by half in order to produce four gamete (egg or sperm) cells. During meiosis, chromosomes engage in a complicated and controlled dance to allow each sperm and egg cell one chromosome. All other cells found in the body have two chromosomes.
In preparation for division, chromosomes group into matching pairs, then cross-over at break points, rejoining their chromosome arms. Crossing over shuffles the deck of DNA, making new combinations between the chromosomes inherited from our parents. This is why children look a bit like their parents, but not exactly.
Hunter's work found new players in meiosis — proteins called SUMO and ubiquitin, and molecular machines called proteasomes.
Ubiquitin is well-known as a small protein "tagging" other proteins to be chopped up by proteasomes and destroyed.
Proteasome molecules also help ensure homologous chromosomes (those with the same structural features and pattern of genes) pair up with each other during meiosis.
SUMO is a close relative to ubiquitin.
Neil Hunter's laboratory at the University of California, Davis College of Biological Sciences, and the lab of Valentine Börner at Cleveland State University, now feel they understand the roles of SUMO, ubiquitin and proteasomes in meiosis.
Altogether, chromosomes have hundreds of potential crossover sites, only a few actually become active. Somehow, the cell narrows the number to a few sites so at least one crossover exists per chromosome.
The new paper was published online Jan. 6 in the journal Science
"When you visualize these proteins under the microscope, they accumulate all along the chromosomes, specifically along the chromosome axes, where all the action is occurring," Hunter said. The chromosome axis is a point on the protein scaffold where DNA is organized into a series of loops. Pairing and crossing over occurs between axes on each set of matching chromosomes.
When chromosomes pair up, SUMO puts a brake on DNA interactions at hundreds of potential crossover sites."Without SUMO, there are no crossovers and meiosis fails. We think that stalling the process provides time to select and mature the crossover sites," Hunter explains.
Ubiquitin and proteasomes release the brake allowing DNA interactions to continue.
The balance of SUMO to ubiquitin allows just those crossovers ensuring each sperm and egg get only one chromosome.
The team worked mostly with cells from mice, including mice where genes associated with SUMO, ubiquitin and related proteins in the process, were genetically "knocked out." Though mice were the model animal used for this discovery, their genes and proteins have counterparts in humans.
Proteasomes and SUMO wrestle chromosomes
Meiosis is the double cell division that generates haploid gametes from diploid parental cells. Pairing of homologous chromosomes during the first meiotic division ensures that each gamete receives a complete set of chromosomes. The proteasome, on the other hand, is a molecular machine that degrades proteins tagged for destruction within the cell (see the Perspective by Zetka). Ahuja et al. show that the proteasome is also involved in ensuring that homologous chromosomes pair with each other during meiosis. Rao et al. show that the SUMO (small ubiquitin-like modifier) protein, ubiquitin, and the proteasome localize to the axes between homologous chromosomes. In this location, they help mediate chromosome pairing and recombination between homologs.
Meiosis produces haploid gametes through a succession of chromosomal events, including pairing, synapsis, and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO (small ubiquitin-like modifier)–modification and ubiquitin-proteasome systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpointlike process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.
First author of the paper is postdoctoral researcher Prasada Rao. The other coauthors are Huanyu Qiao, and several UC Davis undergraduate researchers: Shubhang Bhatt, Logan Bailey, Hung Tran, Sarah Bourne, Wendy Qiu, Anusha Deshpande, Ajay Sharma and Connor Beebout, all working in the Department of Microbiology and Molecular Genetics. Hunter's collaborator, Roberto Pezza, works at the Oklahoma Medical Research Foundation. Hunter holds faculty appointments in the UC Davis Departments of Microbiology and Molecular Genetics and of Molecular and Cellular Biology in the College of Biological Sciences, and at the Department of Cell Biology and Human Anatomy in the School of Medicine. He is affiliated with the UC Davis Comprehensive Cancer Center.
Hunter's work is supported by the Howard Hughes Medical Institute. He was named as a HHMI Early Career Scientist in 2009 and HHMI Investigator in 2013. The National Institute of General Medical Sciences, part of the National Institutes of Health, also supported the study.
Science, issue p. 349, p. 408; see also p. 403
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Jan 31, 2017 Fetal Timeline Maternal Timeline News News Archive
Meiotic DNA replication. Axis proteins associate to form the loop axis structure of DNA.
Image Credit: Research Gate