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Science Advances Oct 2023In almost all sexually reproducing organisms, meiotic recombination and cell division require the synapsis of homologous chromosomes by a large proteinaceous structure,...
In almost all sexually reproducing organisms, meiotic recombination and cell division require the synapsis of homologous chromosomes by a large proteinaceous structure, the synaptonemal complex (SC). While the SC's overall structure is highly conserved across eukaryotes, its constituent proteins diverge between phyla. Transverse filament protein, SYCP1, spans the width of the SC and undergoes amino-terminal head-to-head self-assembly in vitro through a motif that is unusually highly conserved across kingdoms of life. Here, we report creation of mouse mutants, and , that target SYCP1's head-to-head interface. L106E resulted in a complete loss of synapsis, while L102E had no apparent effect on synapsis, in agreement with their differential effects on the SYCP1 head-to-head interface in molecular dynamics simulations. In mice, homologs aligned and recruited low levels of mutant SYCP1 and other SC proteins, but the absence of synapsis led to failure of crossover formation and meiotic arrest. We conclude that SYCP1's conserved head-to-head interface is essential for meiotic chromosome synapsis in vivo.
Topics: Animals; Mice; Chromosome Pairing; Homologous Recombination; Meiosis; Nuclear Proteins; Synaptonemal Complex
PubMed: 37862414
DOI: 10.1126/sciadv.adi1562 -
International Journal of Molecular... Aug 2022Meiosis initiates with the formation of double strand breaks (DSBs) throughout the genome. To avoid genomic instability, these DSBs need to be correctly repaired by...
Meiosis initiates with the formation of double strand breaks (DSBs) throughout the genome. To avoid genomic instability, these DSBs need to be correctly repaired by homologous recombination. Surveillance mechanisms involving the DNA damage response (DDR) pathway ATM-CHK2-p53 can detect the persistence of unrepaired DBSs and activate the recombination-dependent arrest at the pachytene stage. However, a complete understanding of p53 functions under normal physiological conditions remains lacking. Here, we report a detailed analysis of the p53 role during meiotic prophase in mice spermatocytes. We show that the absence of p53 regulates prophase progression by slowing down the pachytene stage when the recombination-dependent arrest occurs. Furthermore, our results show that p53 is necessary for proper crossover (CO) formation and localization. Our study contributes to a deeper understanding of p53 roles during the meiotic prophase.
Topics: Animals; Cell Cycle Proteins; DNA Breaks, Double-Stranded; Male; Meiosis; Mice; Prophase; Spermatocytes; Tumor Suppressor Protein p53
PubMed: 36077210
DOI: 10.3390/ijms23179818 -
Genetics Mar 2018A century of genetic studies of the meiotic process in females has been greatly augmented by both modern molecular biology and major advances in cytology. These... (Review)
Review
A century of genetic studies of the meiotic process in females has been greatly augmented by both modern molecular biology and major advances in cytology. These approaches, and the findings they have allowed, are the subject of this review. Specifically, these efforts have revealed that meiotic pairing in females is not an extension of somatic pairing, but rather occurs by a poorly understood process during premeiotic mitoses. This process of meiotic pairing requires the function of several components of the synaptonemal complex (SC). When fully assembled, the SC also plays a critical role in maintaining homolog synapsis and in facilitating the maturation of double-strand breaks (DSBs) into mature crossover (CO) events. Considerable progress has been made in elucidating not only the structure, function, and assembly of the SC, but also the proteins that facilitate the formation and repair of DSBs into both COs and noncrossovers (NCOs). The events that control the decision to mature a DSB as either a CO or an NCO, as well as determining which of the two CO pathways (class I or class II) might be employed, are also being characterized by genetic and genomic approaches. These advances allow a reconsideration of meiotic phenomena such as interference and the centromere effect, which were previously described only by genetic studies. In delineating the mechanisms by which the oocyte controls the number and position of COs, it becomes possible to understand the role of CO position in ensuring the proper orientation of homologs on the first meiotic spindle. Studies of bivalent orientation have occurred in the context of numerous investigations into the assembly, structure, and function of the first meiotic spindle. Additionally, studies have examined the mechanisms ensuring the segregation of chromosomes that have failed to undergo crossing over.
Topics: Animals; Centromere; Chromosome Painting; Chromosome Pairing; Chromosome Segregation; Crossing Over, Genetic; DNA Breaks, Double-Stranded; Drosophila melanogaster; Female; Meiosis; Oocytes; Recombination, Genetic; Spindle Apparatus; Synaptonemal Complex
PubMed: 29487146
DOI: 10.1534/genetics.117.300081 -
Frontiers in Endocrinology 2023The non-growing, meiotically-arrested oocytes housed within primordial follicles are exquisitely sensitive to genotoxic insults from endogenous and exogenous sources....
INTRODUCTION
The non-growing, meiotically-arrested oocytes housed within primordial follicles are exquisitely sensitive to genotoxic insults from endogenous and exogenous sources. Even a single DNA double-strand break (DSB) can trigger oocyte apoptosis, which can lead to accelerated depletion of the ovarian reserve, early loss of fertility and menopause. Therefore, repair of DNA damage is important for preserving the quality of oocytes to sustain fertility across the reproductive lifespan. This study aimed to evaluate the role of KU80 (encoded by the XRCC5 gene) - an essential component of the non-homologous end joining (NHEJ) pathway - in the repair of oocyte DNA DSBs during reproductive ageing, and following insult caused by the DNA-damaging chemotherapies cyclophosphamide and cisplatin.
METHODS
To investigate the importance of KU80 following endogenous and exogenous DNA damage, ovaries from conditional oocyte-specific knockout ( cKO) and wildtype (WT) mice that were aged or exposed to DNA damage-inducing chemotherapy were compared. Ovarian follicles and oocytes were quantified, morphologically assessed and analysed via immunohistochemistry for markers of DNA damage and apoptosis. In addition, chemotherapy exposed mice were superovulated, and the numbers and quality of mature metaphase- II (MII) oocytes were assessed.
RESULTS
The number of healthy follicles, atretic (dying) follicles, and corpora lutea were similar in Xrcc5 cKO and WT mice at PN50, PN200 and PN300. Additionally, primordial follicle number and ovulation rates were similar in young adult Xrcc5 cKO and WT mice following treatment with cyclophosphamide (75mg/kg), cisplatin (4mg/kg), or vehicle control (saline). Furthermore, KU80 was not essential for the repair of exogenously induced DNA damage in primordial follicle oocytes.
DISCUSSION
These data indicate that KU80 is not required for maintenance of the ovarian reserve, follicle development, or ovulation during maternal ageing. Similarly, this study also indicates that KU80 is not required for the repair of exogenously induced DSBs in the prophase-arrested oocytes of primordial follicles.
Topics: Animals; Female; Mice; Cisplatin; Cyclophosphamide; DNA; Oocytes; Ovarian Follicle; Prophase; Ku Autoantigen
PubMed: 37900135
DOI: 10.3389/fendo.2023.1268009 -
Genes & Development Dec 2020Proper segregation during meiosis requires that homologs be connected by the combination of crossovers and sister chromatid cohesion. To generate crossovers, numerous... (Review)
Review
Proper segregation during meiosis requires that homologs be connected by the combination of crossovers and sister chromatid cohesion. To generate crossovers, numerous double-strand breaks (DSBs) are introduced throughout the genome by the conserved Spo11 endonuclease. DSB formation and its repair are then highly regulated to ensure that homologous chromosomes contain at least one crossover and no DSBs remain prior to meiosis I segregation. The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids. Synapsis occurs when a particular recombination pathway is successful in establishing stable interhomolog connections. In this issue of , Mu and colleagues (pp. 1605-1618) show that SC formation between individual chromosomes provides the feedback to down-regulate Spo11 activity, thereby revealing an additional function for the SC.
Topics: Chromatids; DNA Breaks, Double-Stranded; Homologous Recombination; Meiosis; Synaptonemal Complex
PubMed: 33262143
DOI: 10.1101/gad.345488.120 -
ELife Jan 2023Meiotic chromosome segregation relies on synapsis and crossover (CO) recombination between homologous chromosomes. These processes require multiple steps that are...
Meiotic chromosome segregation relies on synapsis and crossover (CO) recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in , recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break (DSB) induction. Inactivation of CHK-2 terminates DSB formation and enables CO designation and cell cycle progression. These findings illuminate how meiotic cells ensure CO formation and accurate chromosome segregation.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Checkpoint Kinase 2; Chromosome Pairing; Meiosis; Synaptonemal Complex
PubMed: 36700544
DOI: 10.7554/eLife.84492 -
Molecular Phylogenetics and Evolution Dec 2017During the past quarter century, molecular phylogenetic inferences have significantly resolved evolutionary relationships spanning the eukaryotic tree of life. With... (Review)
Review
During the past quarter century, molecular phylogenetic inferences have significantly resolved evolutionary relationships spanning the eukaryotic tree of life. With improved phylogenies in hand, the focus of systematics will continue to expand from estimating species relationships toward examining the evolution of specific, fundamental traits across the eukaryotic tree. Undoubtedly, this will expose knowledge gaps in the evolution of key traits, particularly with respect to non-model lineages. Here, we examine one such trait across eukaryotes-the regulation of homologous chromosome pairing during meiosis-as an illustrative example. Specifically, we present an overview of the breakdown of homologous chromosome pairing in model eukaryotes and provide a discussion of various meiotic aberrations that result in the failure of homolog recognition, with a particular focus on lineages with a history of hybridization and polyploidization, across major eukaryotic clades. We then explore what is known about these processes in natural and non-model eukaryotic taxa, thereby exposing disparities in our understanding of this key trait among non-model groups.
Topics: Chromosome Pairing; Eukaryota; Eukaryotic Cells; Meiosis; Phylogeny; Sequence Homology, Nucleic Acid
PubMed: 28602622
DOI: 10.1016/j.ympev.2017.05.025 -
The Journal of Cell Biology Feb 2021Meiosis creates genetic diversity by recombination and segregation of chromosomes. The synaptonemal complex assembles during meiotic prophase I and assists faithful...
Meiosis creates genetic diversity by recombination and segregation of chromosomes. The synaptonemal complex assembles during meiotic prophase I and assists faithful exchanges between homologous chromosomes, but how its assembly/disassembly is regulated remains to be understood. Here, we report how two major posttranslational modifications, phosphorylation and ubiquitination, cooperate to promote synaptonemal complex assembly. We found that the ubiquitin ligase complex SCF is important for assembly and maintenance of the synaptonemal complex in Drosophila female meiosis. This function of SCF is mediated by two substrate-recognizing F-box proteins, Slmb/βTrcp and Fbxo42. SCF-Fbxo42 down-regulates the phosphatase subunit PP2A-B56, which is important for synaptonemal complex assembly and maintenance.
Topics: Animals; DNA Breaks, Double-Stranded; Down-Regulation; Drosophila Proteins; Drosophila melanogaster; F-Box Proteins; Meiosis; Protein Phosphatase 2; Recombination, Genetic; SKP Cullin F-Box Protein Ligases; Synaptonemal Complex
PubMed: 33382409
DOI: 10.1083/jcb.202009167 -
Cell Cycle (Georgetown, Tex.) 2015During meiotic prophase, DNA double-strand break (DSB) repair-mediated homologous recombination (HR) occurs for exchange of genetic information between homologous... (Review)
Review
During meiotic prophase, DNA double-strand break (DSB) repair-mediated homologous recombination (HR) occurs for exchange of genetic information between homologous chromosomes. Unlike autosomes or female sex chromosomes, human male sex chromosomes X and Y share little homology. Although DSBs are generated throughout male sex chromosomes, homologous recombination does not occur for most regions and DSB repair process is significantly prolonged. As a result, male sex chromosomes are coated with many DNA damage response proteins and form a unique chromatin structure known as the XY body. Interestingly, associated with the prolonged DSB repair, transcription is repressed in the XY body but not in autosomes, a phenomenon known as meiotic sex chromosome inactivation (MSCI), which is critical for male meiosis. Here using mice as model organisms, we briefly summarize recent progress on DSB repair in meiotic prophase and focus on the mechanism and function of DNA damage response in the XY body.
Topics: Animals; Carrier Proteins; Crossing Over, Genetic; DNA Breaks, Double-Stranded; DNA Repair; Male; Mice; Models, Biological; Prophase; Sex Chromosomes; Ubiquitin-Protein Ligases
PubMed: 25565522
DOI: 10.1080/15384101.2014.998070 -
Current Opinion in Plant Biology Apr 2017Meiotic recombination ensures the fertility of gametes and creates novel genetic combinations. Although meiotic crossover (CO) frequency is under homeostatic control, CO... (Review)
Review
Meiotic recombination ensures the fertility of gametes and creates novel genetic combinations. Although meiotic crossover (CO) frequency is under homeostatic control, CO frequency is also plastic in nature and can respond to environmental conditions. Most investigations have focused on temperature and recombination, but other external and internal stimuli also have important roles in modulating CO frequency. Even less is understood about the molecular mechanisms that underly these phenomenon, but recent work has begun to advance our knowledge in this field. In this review, we identify and explore potential mechanisms including changes in: the synaptonemal complex, chromatin state, DNA methylation, and RNA splicing.
Topics: Animals; Crossing Over, Genetic; DNA Methylation; Meiosis; Stress, Physiological; Synaptonemal Complex
PubMed: 28258986
DOI: 10.1016/j.pbi.2016.11.019