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BioRxiv : the Preprint Server For... May 2024The meiosis-specific kinase Mek1 regulates key steps in meiotic recombination in the budding yeast, limits resection at the double strand break (DSB) ends and is...
The meiosis-specific kinase Mek1 regulates key steps in meiotic recombination in the budding yeast, limits resection at the double strand break (DSB) ends and is required for preferential strand invasion into homologs, a process known as interhomolog bias. After strand invasion, promotes phosphorylation of the synaptonemal complex protein Zip1 that is necessary for DSB repair mediated by a crossover specific pathway that enables chromosome synapsis. In addition, Mek1 phosphorylation of the meiosis-specific transcription factor, Ndt80, regulates the meiotic recombination checkpoint that prevents exit from pachytene when DSBs are present. Mek1 interacts with Ndt80 through a five amino acid sequence, RPSKR, located between the DNA binding and activation domains of Ndt80. AlphaFold Multimer modeling of a fragment of Ndt80 containing the RPSKR motif and full length Mek1 indicated that RPSKR binds to an acidic loop located in the Mek1 FHA domain, a non-canonical interaction with this motif. A second protein, the 5'-3' helicase Rrm3, similarly interacts with Mek1 through an RPAKR motif and is an in vitro substrate of Mek1. Genetic analysis using various mutants in the acidic loop validated the AlphaFold model, in that they specifically disrupt two-hybrid interactions with Ndt80 and Rrm3. Phenotypic analyses further showed that the acidic loop mutants are defective in the meiotic recombination checkpoint, and in certain circumstances exhibit more severe phenotypes compared to the mutant with the RPSKR sequence deleted, suggesting that additional, as yet unknown, substrates of Mek1 also bind to Mek1 using an RPXKR motif.
PubMed: 38826409
DOI: 10.1101/2024.05.24.595751 -
Zoological Science Jun 2024Formation of the synaptonemal complex (SC) is a prerequisite for proper recombination and chromosomal segregation during meiotic prophase I. One mechanism that ensures...
Formation of the synaptonemal complex (SC) is a prerequisite for proper recombination and chromosomal segregation during meiotic prophase I. One mechanism that ensures SC formation is chromosomal movement, which is driven by the force derived from cytoskeletal motors. Here, we report the phenotype of medaka mutants lacking the telomere repeat binding bouquet formation protein 1 (TERB1), which, in combination with the SUN/KASH protein, mediates chromosomal movement by connecting telomeres and cytoskeletal motors. Mutations in the gene exhibit defects in SC formation in medaka. Although SC formation was initiated, as seen by the punctate lateral elements and fragmented transverse filaments, it was not completed in the mutant meiocytes. The mutant phenotype further revealed that the introduction of double strand breaks was independent of synapsis completion. In association with these phenotypes, meiocytes in both the ovaries and testes exhibited an aberrant arrangement of homologous chromosomes. Interestingly, although oogenesis halted at the zygotene-like stage in mutant, testes continued to produce sperm-like cells with aberrant DNA content. This indicates that the mechanism of meiotic checkpoint is sexually different in medaka, similar to the mammalian checkpoint in which oogenesis proceeds while spermatogenesis is arrested. Moreover, our results suggest that spermatogenesis is mechanistically dissociable from meiosis.
Topics: Animals; Oryzias; Synaptonemal Complex; Male; Gametogenesis; Female; Mutation; Meiosis; Fish Proteins
PubMed: 38809870
DOI: 10.2108/zs230108 -
Life Science Alliance Aug 2024Homologous recombination is a major pathway for the repair of DNA double strand breaks, essential both to maintain genomic integrity and to generate genetic diversity....
Homologous recombination is a major pathway for the repair of DNA double strand breaks, essential both to maintain genomic integrity and to generate genetic diversity. Mechanistically, homologous recombination involves the use of a homologous DNA molecule as a template to repair the break. In eukaryotes, the search for and invasion of the homologous DNA molecule is carried out by two recombinases, RAD51 in somatic cells and RAD51 and DMC1 in meiotic cells. During recombination, the recombinases bind overhanging single-stranded DNA ends to form a nucleoprotein filament, which is the active species in promoting DNA invasion and strand exchange. RAD51 and DMC1 carry two major DNA-binding sites-essential for nucleofilament formation and DNA strand exchange, respectively. Here, we show that the function of RAD51 DNA-binding site II is conserved in the plant, Arabidopsis. Mutation of three key amino acids in site II does not affect RAD51 nucleofilament formation but inhibits its recombinogenic activity, analogous to results from studies of the yeast and human proteins. We further confirm that recombinogenic function of RAD51 DNA-binding site II is not required for meiotic double-strand break repair when DMC1 is present. The Arabidopsis separation of function mutant shows a dominant negative phenotype, pointing to distinct biochemical properties of eukaryotic RAD51 proteins.
Topics: Arabidopsis; Rad51 Recombinase; Arabidopsis Proteins; Binding Sites; Homologous Recombination; Mutation; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Meiosis; Cell Cycle Proteins; DNA Repair
PubMed: 38803223
DOI: 10.26508/lsa.202402701 -
Molecular Aspects of Medicine Jun 2024Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic... (Review)
Review
Meiosis is a critical step for spermatogenesis and oogenesis. Meiosis commences with pre-meiotic S phase that is subsequently followed by meiotic prophase. The meiotic prophase is characterized by the meiosis-specific chromosomal events such as chromosome recombination and homolog synapsis. Meiosis initiator (MEIOSIN) and stimulated by retinoic acid gene 8 (STRA8) initiate meiosis by activating the meiotic genes by installing the meiotic prophase program at pre-meiotic S phase. This review highlights the mechanisms of meiotic initiation and meiotic prophase progression from the point of the gene expression program and its relevance to infertility. Furthermore, upstream pathways that regulate meiotic initiation will be discussed in the context of spermatogenic development, indicating the sexual differences in the mode of meiotic entry.
Topics: Spermatogenesis; Humans; Meiosis; Animals; Male; Meiotic Prophase I; Prophase
PubMed: 38797021
DOI: 10.1016/j.mam.2024.101282 -
PLoS Genetics May 2024Molecular dissection of meiotic recombination in mammals, combined with population-genetic and comparative studies, have revealed a complex evolutionary dynamic...
Molecular dissection of meiotic recombination in mammals, combined with population-genetic and comparative studies, have revealed a complex evolutionary dynamic characterized by short-lived recombination hotspots. Hotspots are chromosome positions containing DNA sequences where the protein PRDM9 can bind and cause crossing-over. To explain these fast evolutionary dynamic, a so-called intra-genomic Red Queen model has been proposed, based on the interplay between two antagonistic forces: biased gene conversion, mediated by double-strand breaks, resulting in hotspot extinction (the hotspot conversion paradox), followed by positive selection favoring mutant PRDM9 alleles recognizing new sequence motifs. Although this model predicts many empirical observations, the exact causes of the positive selection acting on new PRDM9 alleles is still not well understood. In this direction, experiment on mouse hybrids have suggested that, in addition to targeting double strand breaks, PRDM9 has another role during meiosis. Specifically, PRDM9 symmetric binding (simultaneous binding at the same site on both homologues) would facilitate homology search and, as a result, the pairing of the homologues. Although discovered in hybrids, this second function of PRDM9 could also be involved in the evolutionary dynamic observed within populations. To address this point, here, we present a theoretical model of the evolutionary dynamic of meiotic recombination integrating current knowledge about the molecular function of PRDM9. Our modeling work gives important insights into the selective forces driving the turnover of recombination hotspots. Specifically, the reduced symmetrical binding of PRDM9 caused by the loss of high affinity binding sites induces a net positive selection eliciting new PRDM9 alleles recognizing new targets. The model also offers new insights about the influence of the gene dosage of PRDM9, which can paradoxically result in negative selection on new PRDM9 alleles entering the population, driving their eviction and thus reducing standing variation at this locus.
Topics: Histone-Lysine N-Methyltransferase; Meiosis; Animals; Evolution, Molecular; Mice; Gene Conversion; DNA Breaks, Double-Stranded; Alleles; Models, Genetic; Humans; Recombination, Genetic
PubMed: 38768268
DOI: 10.1371/journal.pgen.1011274 -
Yi Chuan = Hereditas Dec 2023Normal oogenesis is crucial to successful reproduction. During the human female fetal stage, primordial germ cells transform from mitosis to meiosis. After synapsis and... (Review)
Review
Normal oogenesis is crucial to successful reproduction. During the human female fetal stage, primordial germ cells transform from mitosis to meiosis. After synapsis and recombination of homologous chromosomes, meiosis is arrested at the diplotene stage of prophase in meiosis I. The maintenance of oocyte meiotic arrest in the follicle is primarily attributed to high cytoplasmic concentrations of cyclic adenosine monophosphate. During the menstrual cycle, follicle-stimulating hormone and luteinizing hormone lead to the resumption of meiosis that occurs in certain oocytes and complete the ovulation process. Anything that disturbs oocyte meiosis may result in failure of oogenesis and seriously affect both the fertilization and embryonic development. The rapid development of the assisted reproduction technology, high-throughput sequencing technology, and molecular biology technology provide new ideas and means for human to understand molecular mechanism of meiosis and diagnosis and treatment of oocyte maturation defects. In this review, we mainly summarize the recent physiological and pathological mechanisms of oogenesis, involving homologous recombination, meiotic arrest and resumption, maternal mRNA degradation, post-translational regulation, zona pellucida assembly, and so on. We wish to take this opportunity to raise the awareness of researchers in related fields on oocyte meiosis, providing a theoretical basis for further research and disease treatments.
Topics: Meiosis; Oocytes; Humans; Female; Oogenesis; Animals
PubMed: 38764273
DOI: 10.16288/j.yczz.23-170 -
Genetics May 2024Chromosome inversions are of unique importance in the evolution of genomes and species because when heterozygous with a standard arrangement chromosome, they suppress...
Chromosome inversions are of unique importance in the evolution of genomes and species because when heterozygous with a standard arrangement chromosome, they suppress meiotic crossovers within the inversion. In Drosophila species, heterozygous inversions also cause the interchromosomal effect, whereby the presence of a heterozygous inversion induces a dramatic increase in crossover frequencies in the remainder of the genome within a single meiosis. To date, the interchromosomal effect has been studied exclusively in species that also have high frequencies of inversions in wild populations. We took advantage of a recently developed approach for generating inversions in Drosophila simulans, a species that does not have inversions in wild populations, to ask if there is an interchromosomal effect. We used the existing chromosome 3R balancer and generated a new chromosome 2L balancer to assay for the interchromosomal effect genetically and cytologically. We found no evidence of an interchromosomal effect in D. simulans. To gain insight into the underlying mechanistic reasons, we qualitatively analyzed the relationship between meiotic double-strand break formation and synaptonemal complex assembly. We find that the synaptonemal complex is assembled prior to double-strand break formation as in D. melanogaster; however, we show that the synaptonemal complex is assembled prior to localization of the oocyte determination factor Orb, whereas in D. melanogaster, synaptonemal complex formation does not begin until Orb is localized. Together, our data show no evidence that heterozygous inversions in D. simulans induce an interchromosomal effect and that there are differences in the developmental programming of the early stages of meiosis.
PubMed: 38762892
DOI: 10.1093/genetics/iyae084 -
PLoS Computational Biology May 2024During meiosis, pairing of homologous chromosomes (homologs) ensures the formation of haploid gametes from diploid precursor cells, a prerequisite for sexual...
During meiosis, pairing of homologous chromosomes (homologs) ensures the formation of haploid gametes from diploid precursor cells, a prerequisite for sexual reproduction. Pairing during meiotic prophase I facilitates crossover recombination and homolog segregation during the ensuing reductional cell division. Mechanisms that ensure stable homolog alignment in the presence of an excess of non-homologous chromosomes have remained elusive, but rapid chromosome movements appear to play a role in the process. Apart from homolog attraction, provided by early intermediates of homologous recombination, dissociation of non-homologous associations also appears to contribute to homolog pairing, as suggested by the detection of stable non-homologous chromosome associations in pairing-defective mutants. Here, we have developed an agent-based model for homolog pairing derived from the dynamics of a naturally occurring chromosome ensemble. The model simulates unidirectional chromosome movements, as well as collision dynamics determined by attractive and repulsive forces arising from close-range physical interactions. Chromosome number and size as well as movement velocity and repulsive forces are identified as key factors in the kinetics and efficiency of homologous pairing in addition to homolog attraction. Dissociation of interactions between non-homologous chromosomes may contribute to pairing by crowding homologs into a limited nuclear area thus creating preconditions for close-range homolog attraction. Incorporating natural chromosome lengths, the model accurately recapitulates efficiency and kinetics of homolog pairing observed for wild-type and mutant meiosis in budding yeast, and can be adapted to nuclear dimensions and chromosome sets of other organisms.
Topics: Meiosis; Chromosome Pairing; Models, Genetic; Saccharomyces cerevisiae; Chromosomes, Fungal; Cell Nucleus; Computer Simulation; Computational Biology
PubMed: 38739641
DOI: 10.1371/journal.pcbi.1011416 -
Animals : An Open Access Journal From... Apr 2024Meiotic recombination is a prevalent process in eukaryotic sexual reproduction organisms that plays key roles in genetic diversity, breed selection, and species...
Meiotic recombination is a prevalent process in eukaryotic sexual reproduction organisms that plays key roles in genetic diversity, breed selection, and species evolution. However, the recombination events differ across breeds and even within breeds. In this study, we initially computed large-scale population recombination rates of both sexes using approximately 52 K SNP genotypes in a total of 3279 pigs from four different Chinese and Western breeds. We then constructed a high-resolution historical recombination map using approximately 16 million SNPs from a sample of unrelated individuals. Comparative analysis of porcine recombination events from different breeds and at different resolutions revealed the following observations: Firstly, the 1Mb-scale pig recombination maps of the same sex are moderately conserved among different breeds, with the similarity of recombination events between Western pigs and Chinese indigenous pigs being lower than within their respective groups. Secondly, we identified 3861 recombination hotspots in the genome and observed medium- to high-level correlation between historical recombination rates (0.542~0.683) and estimates of meiotic recombination rates. Third, we observed that recombination hotspots are significantly far from the transcription start sites of pig genes, and the silico-predicted zinc finger domain DNA recognition motif is significantly enriched in the regions of recombination hotspots compared to recombination coldspots, highlighting the potential role of in regulating recombination hotspots in pigs. Our study analyzed the variation patterns of the pig recombination map at broad and fine scales, providing a valuable reference for genomic selection breeding and laying a crucial foundation for further understanding the molecular mechanisms of pig genome recombination.
PubMed: 38731349
DOI: 10.3390/ani14091345 -
Plant Physiology May 2024
PubMed: 38718098
DOI: 10.1093/plphys/kiae266