scholarly journals Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility

2020 ◽  
Vol 6 (36) ◽  
pp. eabb1660
Author(s):  
Fernando Sánchez-Sáez ◽  
Laura Gómez-H ◽  
Orla M. Dunne ◽  
Cristina Gallego-Páramo ◽  
Natalia Felipe-Medina ◽  
...  
Keyword(s):  
Meiotic Chromosome ◽  
Central Element ◽  
Mouse Genetics ◽  
Structural Components ◽  
Targeted Deletion ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
N Terminus ◽  
Binding Interfaces ◽  
Reductional Division

Meiotic reductional division depends on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC has eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine mouse genetics, cellular, and biochemical studies to reveal that SYCE1 undergoes multivalent interactions with SC component SIX6OS1. The N terminus of SIX6OS1 binds and disrupts SYCE1’s core dimeric structure to form a 1:1 complex, while their downstream sequences provide a distinct second interface. These interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure (POF), respectively. Mice harboring SYCE1’s POF mutation and a targeted deletion within SIX6OS1’s N terminus are infertile with failure of chromosome synapsis. We conclude that both SYCE1-SIX6OS1 binding interfaces are essential for SC assembly, thus explaining how SYCE1’s reported clinical mutations give rise to human infertility.

scholarly journals Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility

2020 ◽  
Author(s):  
Fernando Sánchez-Sáez ◽  
Laura Gómez-H ◽  
Orla M. Dunne ◽  
Cristina Gallego-Páramo ◽  
Natalia Felipe-Medina ◽  
...  
Keyword(s):  
Meiotic Chromosome ◽  
Central Element ◽  
Mouse Genetics ◽  
Obstructive Azoospermia ◽  
Targeted Deletion ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
N Terminus ◽  
Binding Interfaces ◽  
Reductional Division

AbstractMeiotic reductional division is dependent on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC is formed of eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine mouse genetics, cellular and biochemical studies to reveal that SYCE1 undergoes multivalent interactions with SC component SIX6OS1. The N-terminus of SIX6OS1 binds and disrupts SYCE1’s core dimeric structure to form a 1:1 complex, whilst their downstream sequences provide a distinct second interface. These interfaces are separately disrupted by SYCE1 mutations associated with non-obstructive azoospermia and premature ovarian failure, respectively. Mice harbouring SYCE1’s POF mutation and a targeted deletion within SIX6OS1’s N-terminus are infertile with failure of chromosome synapsis. We conclude that both SYCE1-SIX6OS1 binding interfaces are essential for SC assembly, thus explaining how SYCE1’s reported clinical mutations give rise to human infertility.

scholarly journals Quantitative basis of meiotic chromosome synapsis analyzed by electron tomography

2019 ◽  
Author(s):  
Marie-Christin Spindler ◽  
Sebastian Filbeck ◽  
Christian Stigloher ◽  
Ricardo Benavente
Keyword(s):  
Central Region ◽  
3D Model ◽  
Electron Tomography ◽  
Meiotic Chromosome ◽  
Topological Analysis ◽  
Central Element ◽  
Morphological Data ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Quantitative Basis

AbstractThe synaptonemal complex is a multiprotein complex, which mediates the synapsis and recombination between homologous chromosomes during meiosis. The complex is comprised of two lateral elements and a central element connected by perpendicular transverse filaments (TFs). A 3D model based on actual morphological data of the SC is missing. Here, we applied electron tomography (ET) and manual feature extraction to generate a quantitative 3D model of the murine SC. We quantified the length (90 nm) and width (2 nm) of the TFs. Interestingly, the 80 TFs/μm are distributed asymmetrically in the central region of the SC challenging available models of SC organization. Furthermore, our detailed 3D topological analysis does not support a bilayered organization of the central region as proposed earlier. Overall, our quantitative analysis is relevant to understand the functions and dynamics of the SC and provides the basis for analyzing multiprotein complexes in their morphological context using ET.

scholarly journals Quantitative basis of meiotic chromosome synapsis analyzed by electron tomography

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marie-Christin Spindler ◽  
Sebastian Filbeck ◽  
Christian Stigloher ◽  
Ricardo Benavente
Keyword(s):  
Central Region ◽  
3D Model ◽  
Electron Tomography ◽  
Meiotic Chromosome ◽  
Topological Analysis ◽  
Central Element ◽  
Morphological Data ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Quantitative Basis

Abstract The synaptonemal complex is a multiprotein complex, which mediates the synapsis and recombination between homologous chromosomes during meiosis. The complex is comprised of two lateral elements and a central element connected by perpendicular transverse filaments (TFs). A 3D model based on actual morphological data of the SC is missing. Here, we applied electron tomography (ET) and manual feature extraction to generate a quantitative 3D model of the murine SC. We quantified the length (90 nm) and width (2 nm) of the TFs. Interestingly, the 80 TFs/µm are distributed asymmetrically in the central region of the SC challenging available models of SC organization. Furthermore, our detailed 3D topological analysis does not support a bilayered organization of the central region as proposed earlier. Overall, our quantitative analysis is relevant to understand the functions and dynamics of the SC and provides the basis for analyzing multiprotein complexes in their morphological context using ET.

scholarly journals A pseudo-meiotic centrosomal function of TEX12 in cancer

2019 ◽  
Author(s):  
S Sandhu ◽  
LJ Salmon ◽  
JE Hunter ◽  
CL Wilson ◽  
ND Perkins ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Meiotic Chromosome ◽  
Cancer Therapeutics ◽  
Structural Protein ◽  
Multiple Cancer ◽  
Aberrant Expression ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Cancer Models ◽  
The Many

AbstractCell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes1, 2. The many meiosis-specific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer3, 4. Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis5–7, is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis. We find that TEX12 knock-down causes proliferative failure in multiple cancer cell lines, and confirm its role in the early stages of oncogenesis through murine cancer models. Remarkably, somatically expressed TEX12 localises to centrosomes, leading to altered centrosome number and structure, features associated with cancer development. Further, we identify TEX12 in meiotic centrin-rich bodies, likely precursors of the mitotic centrosome, suggesting that this may represent an additional cellular function of TEX12 in meiosis that has been previously overlooked. Thus, we propose that an otherwise meiotic function of TEX12 in centrosome duplication is responsible for promoting oncogenesis and cellular proliferation in cancer, which may be targeted for novel cancer therapeutics and diagnostics.

scholarly journals Modulation of Prdm9-controlled meiotic chromosome asynapsis overrides hybrid sterility in mice

2017 ◽  
Author(s):  
Sona Gregorova ◽  
Vaclav Gergelits ◽  
Irena Chvatalova ◽  
Tanmoy Bhattacharyya ◽  
Barbora Valiskova ◽  
...  
Keyword(s):  
Meiotic Chromosome ◽  
Hybrid Sterility ◽  
Mouse Strains ◽  
Dna Double Strand Breaks ◽  
Closely Related Species ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Recombination Hotspots ◽  
Chromosome Synapsis ◽  
Reproductive Isolation Mechanisms

AbstractThe infertility of hybrids between closely related species is one of the reproductive isolation mechanisms leading to speciation. Prdm9, the only known vertebrate hybrid sterility gene causes failure of meiotic chromosome synapsis and infertility in male hybrids between mouse strains derived from two mouse subspecies. Within species Prdm9 determines the sites of programmed DNA double-strand breaks and meiotic recombination hotspots. To investigate the relation between Prdm9-controlled meiotic arrest and asynapsis, we inserted random stretches of consubspecific homology on several autosomal pairs in sterile hybrids and analyzed their ability to form synaptonemal complexes and rescue male fertility. Twenty-seven or more Mb of consubspecific homology fully restored synapsis in a given autosomal pair and we predicted that two symmetric DSBs or more per chromosome are necessary for successful meiosis. We hypothesize that impaired recombination between evolutionary diverged homologous chromosomes could function as one of the mechanisms of hybrid sterility occurring in various sexually reproducing species.

Nucleolus-associated telomere clustering and pairing precede meiotic chromosome synapsis in Arabidopsis thaliana

2001 ◽  
Vol 114 (23) ◽  
pp. 4207-4217 ◽  
Author(s):  
Susan J. Armstrong ◽  
F. Christopher H. Franklin ◽  
Gareth H. Jones
Keyword(s):  
Arabidopsis Thaliana ◽  
Meiotic Chromosome ◽  
In Situ Hybridisation ◽  
Embryo Sac ◽  
Early Prophase ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Mother Cells ◽  
Telomere Signal

The intranuclear arrangements of centromeres and telomeres during meiotic interphase and early prophase I of meiosis in Arabidopsis thaliana were analysed by fluorescent in situ hybridisation to spread pollen mother cells and embryo-sac mother cells. Meiocyte identification, staging and progression were established by spreading and sectioning techniques, including various staining procedures and bromodeoxyuridine labeling of replicating DNA. Centromere regions of Arabidopsis are unpaired, widely dispersed and peripherally located in nuclei during meiotic interphase, and they remain unpaired and unassociated throughout leptotene. Eventually they associate pairwise during zygotene, as part of the nucleus-wide synapsis of homologous chromosomes. Telomeres, by contrast, show a persistent association with the nucleolus throughout meiotic interphase. Variation in telomere signal number indicates that telomeres undergo pairing during this interval, preceding the onset of general chromosome synapsis. During leptotene the paired telomeres lose their association with the nucleolus and become widely dispersed. As the chromosomes synapse during zygotene, the telomeres reveal a loose clustering within one hemisphere, which may represent a degenerate or relic bouquet configuration. We propose that in Arabidopsis the classical leptotene/zygotene bouquet is absent and is replaced functionally by nucleolus-associated telomere clustering.

scholarly journals The rec102 mutant of yeast is defective in meiotic recombination and chromosome synapsis.

Genetics ◽  
1992 ◽  
Vol 130 (1) ◽  
pp. 59-69
Author(s):  
J Bhargava ◽  
J Engebrecht ◽  
G S Roeder
Keyword(s):  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Recombination ◽  
Meiotic Chromosome ◽  
Crossing Over ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Recombination Pathway ◽  
Yeast Mutants ◽  
Meiosis I

Abstract A mutation at the REC102 locus was identified in a screen for yeast mutants that produce inviable spores. rec102 spore lethality is rescued by a spo13 mutation, which causes cells to bypass the meiosis I division. The rec102 mutation completely eliminates meiotically induced gene conversion and crossing over but has no effect on mitotic recombination frequencies. Cytological studies indicate that the rec102 mutant makes axial elements (precursors to the synaptonemal complex), but homologous chromosomes fail to synapse. In addition, meiotic chromosome segregation is significantly delayed in rec102 strains. Studies of double and triple mutants indicate that the REC102 protein acts before the RAD52 gene product in the meiotic recombination pathway. The REC102 gene was cloned based on complementation of the mutant defect and the gene was mapped to chromosome XII between CDC25 and STE11.

scholarly journals Crossover recombination and synapsis are linked by adjacent regions within the N terminus of the Zip1 synaptonemal complex protein

2018 ◽  
Author(s):  
Karen Voelkel-Meiman ◽  
Shun-Yun Cheng ◽  
Melanie Parziale ◽  
Savannah J. Morehouse ◽  
Arden Feil ◽  
...  
Keyword(s):  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Central Element ◽  
Building Blocks ◽  
Homologous Chromosomes ◽  
Sumo Ligase ◽  
Close Proximity ◽  
N Terminus ◽  
Complex Protein ◽  
Synaptonemal Complex Protein

AbstractAccurate chromosome segregation during meiosis relies on the prior establishment of at least one crossover recombination event between homologous chromosomes, which is often associated with the meiosis-specific MutSγ complex. The recombination intermediates that give rise to MutSγ interhomolog crossovers are embedded within a hallmark meiotic prophase structure called the synaptonemal complex (SC), but the mechanisms that coordinate the processes of SC assembly (synapsis) and crossover recombination remain poorly understood. Among known central region building blocks of the budding yeast SC, the Zip1 protein is unique for its SC-independent role in promoting MutSγ crossovers. Here we report that adjacent regions within Zip1’s unstructured N terminus encompass its crossover and SC assembly functions. We previously showed that deletion of Zip1 residues 21-163 abolishes tripartite SC assembly and prevents the robust SUMOylation of the SC central element component, Ecm11, but allows excess MutSγ crossover recombination. We find the reciprocal phenotype when Zip1 residues 2-9 or 10-14 are deleted; in these mutants SC assembles and Ecm11 is hyperSUMOylated, but MutSγ crossovers are strongly diminished. Interestingly, Zip1 residues 2-9 or 2-14 are required for the normal localization of Zip3, a putative E3 SUMO ligase and pro-MutSγ crossover factor, to Zip1 polycomplex structures and to recombination initiation sites. By contrast, deletion of Zip1 residues 15-20 does not detectably prevent Zip3’s localization at Zip1 polycomplex and supports some MutSγ crossing over but prevents normal SC assembly and robust Ecm11 SUMOylation. These results highlight distinct N terminal regions that are differentially critical for Zip1’s roles in crossover recombination and SC assembly; we speculate that the adjacency of these regions enables Zip1 to serve as a liaison, facilitating crosstalk between the two processes by bringing crossover recombination and synapsis factors in close proximity to one another.

scholarly journals Recombination Can Partially Substitute for SPO13 in Regulating Meiosis I in Budding Yeast

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1607-1621 ◽  
Author(s):  
Lisa Henninger Rutkowski ◽  
Rochelle Easton Esposito
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nuclear Division ◽  
Crossing Over ◽  
Wild Type Allele ◽  
Null Mutant ◽  
Wild Type ◽  
Homologous Chromosomes ◽  
Chromosome Synapsis ◽  
Reductional Division ◽  
Meiosis I

Abstract Recombination and chromosome synapsis bring homologous chromosomes together, creating chiasmata that ensure accurate disjunction during reductional division. SPO13 is a key gene required for meiosis I (MI) reductional segregation, but dispensable for recombination, in Saccharomyces cerevisiae. Absence of SPO13 leads to single-division meiosis where reductional segregation is largely eliminated, but other meiotic events occur relatively normally. This phenotype allows haploids to produce viable meiotic products. Spo13p is thought to act by delaying nuclear division until sister centromeres/chromatids undergo proper cohesion for segregation to the same pole at MI. In the present study, a search for new spo13-like mutations that allow haploid meiosis recovered only new spo13 alleles. Unexpectedly, an unusual reduced-expression allele (spo13-23) was recovered that behaves similarly to a null mutant in haploids but to a wild-type allele in diploids, dependent on the presence of recombining homologs rather than on a diploid genome. This finding demonstrates that in addition to promoting accurate homolog disjunction, recombination can also function to partially substitute for SPO13 in promoting sister cohesion. Analysis of various recombination-defective mutants indicates that this contribution of recombination to reductional segregation requires full levels of crossing over. The implications of these results regarding SPO13 function are discussed.

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