HTP-1M127K is not loaded to the axial element of meiotic chromosomes (top panel), but promotes efficient recruitment of Polo-like kinase 2 to pairing center regions (bottom panel).
The CSC’s Meiosis Group has shown that a protein called HTP-1 plays a key role in reducing errors during meiosis by monitoring the status of chromosome pairing.
The study, which was published on the 6 November in Developmental Cell, found that HTP-1 participates in a checkpoint that regulates progression during early meiosis, the specialised cell division program that forms the sex cells.
The HTP-1 protein ensures that homologous chromosomes – those that are genetically similar – have paired up correctly before the cell can progress onto the next stage of meiosis, when the cell undergoes two consecutive divisions. Errors at the ‘homologue pairing’ stage can lead to sperm and egg cells with an incorrect number of chromosomes, one of the leading causes of sterility and birth defects such as Down’s syndrome.
The process of pairing up is like a dance, says Enrique Martinez-Perez, who leads the Meiosis Group. Chromosomes move around the dance floor of the cell’s nucleus until they find the correct partner, a homologous chromosome. Once chromosomes have paired up correctly, a protein structure known as the synaptonemal complex glues them together.
“In mutants that don’t have the HTP-1 protein, chromosome homology is completely disregarded. For example, Chromosome 1 might build a synaptonemal complex with Chromosome 3,” says Martinez-Perez.
The researchers also made the unexpected discovery that a mutant form of HTP-1, which fails to bind to chromosomes, plays a role in the pairing checkpoint. This suggests that HTP-1 can behave as a soluble signalling molecule, rather than working by binding to chromosomes as previously thought.
“Now we have clear evidence that nuclear soluble HTP-1 is a component of a checkpoint that delays the cell cycle if homologues are not paired up, extending the period of homology search and preventing the installation of the synaptonemal complex between non-homologous chromosomes. Moving forwards, we need to identify the other proteins that are required to regulate early meiotic progression,” he adds.
The researchers also draw a clear analogy between the role of HTP-1 in coupling homologue pairing with meiotic progression and the role of the Mad2 protein in the spindle assembly checkpoint, which ensures that all chromosomes are correctly attached to microtubules before a cell can divide.
Martinez-Perez’s group worked in collaboration with the CSC’s Proteomics Facility, Christian Speck’s DNA Replication Group at CSC/Imperial College, and the Department of Biochemistry at Oxford University.
Publication: Nicola Silva, Nuria Ferrandiz,Consuelo Barroso, Silvia Tognetti, James Lightfoot, Oana Telecan, Vesela Encheva, Peter Faull, Simon Hanni, Andre Furger, Ambrosius P. Snijders, Christian Speck, Enrique Martinez-Perez: The Fidelity of Synaptonemal Complex Assembly Is Regulated by a Signaling Mechanism that Controls Early Meiotic Progression, Developmental Cell, doi: http://dx.doi.org/10.1016/j.devcel.2014.10.001
The work was supported by a BBSRC David Phillips fellowship and an MRC core-funded grant.
The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk
