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Frontiers in Cell and Developmental... 2021Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia.... (Review)
Review
Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.
PubMed: 33763429
DOI: 10.3389/fcell.2021.652407 -
Cells Jun 2023The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC... (Review)
Review
The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC mediates the synapses of the homologous chromosomes, leading to the formation of bivalents, and physically supports the formation of programmed double-strand breaks (DSBs) and their subsequent repair and maturation into crossovers (COs), which are essential for genome haploidization. Defects in the assembly of the SC or in the function of the associated meiotic recombination machinery can lead to meiotic arrest and human infertility. The majority of proteins and complexes involved in these processes are exclusively expressed during meiosis or harbor meiosis-specific subunits, although some have dual functions in somatic DNA repair and meiosis. Consistent with their functions, aberrant expression and malfunctioning of these genes have been associated with cancer development. In this review, we focus on the significance of the SC and their meiotic-associated proteins in human fertility, as well as how human genetic variants encoding for these proteins affect the meiotic process and contribute to infertility and cancer development.
Topics: Synaptonemal Complex; Humans; Meiosis; Neoplasms; Infertility; Male; Female; Recombination, Genetic
PubMed: 37443752
DOI: 10.3390/cells12131718 -
Asian Journal of Andrology 2021Repairing DNA double-strand breaks (DSBs) with homologous chromosomes as templates is the hallmark of meiosis. The critical outcome of meiotic homologous recombination... (Review)
Review
Repairing DNA double-strand breaks (DSBs) with homologous chromosomes as templates is the hallmark of meiosis. The critical outcome of meiotic homologous recombination is crossovers, which ensure faithful chromosome segregation and promote genetic diversity of progenies. Crossover patterns are tightly controlled and exhibit three characteristics: obligatory crossover, crossover interference, and crossover homeostasis. Aberrant crossover patterns are the leading cause of infertility, miscarriage, and congenital disease. Crossover recombination occurs in the context of meiotic chromosomes, and it is tightly integrated with and regulated by meiotic chromosome structure both locally and globally. Meiotic chromosomes are organized in a loop-axis architecture. Diverse evidence shows that chromosome axis length determines crossover frequency. Interestingly, short chromosomes show different crossover patterns compared to long chromosomes. A high frequency of human embryos are aneuploid, primarily derived from female meiosis errors. Dramatically increased aneuploidy in older women is the well-known "maternal age effect." However, a high frequency of aneuploidy also occurs in young women, derived from crossover maturation inefficiency in human females. In addition, frequency of human aneuploidy also shows other age-dependent alterations. Here, current advances in the understanding of these issues are reviewed, regulation of crossover patterns by meiotic chromosomes are discussed, and issues that remain to be investigated are suggested.
Topics: Cell Division; Chromosome Segregation; Humans; Meiosis; Recombination, Genetic
PubMed: 33533735
DOI: 10.4103/aja.aja_86_20 -
Current Topics in Developmental Biology 2023Chromosomes adopt specific conformations to regulate various cellular processes. A well-documented chromosome configuration is the highly compacted chromosome structure... (Review)
Review
Chromosomes adopt specific conformations to regulate various cellular processes. A well-documented chromosome configuration is the highly compacted chromosome structure during metaphase. More regional chromatin conformations have also been reported, including topologically associated domains encompassing mega-bases of DNA and local chromatin loops formed by kilo-bases of DNA. In this review, we discuss the changes in chromatin conformation taking place between somatic and meiotic cells, with a special focus on the establishment of a proteinaceous structure, called the chromosome axis, at the beginning of meiosis. The chromosome axis is essential to support key meiotic processes such as chromosome pairing, homologous recombination, and balanced chromosome segregation to transition from a diploid to a haploid stage. We review the role of the chromosome axis in meiotic chromatin organization and provide a detailed description of its protein composition. We also review the conserved and distinct roles between species of axis proteins in meiotic recombination, which is a major factor contributing to the creation of genetic diversity and genome evolution. Finally, we discuss situations where the chromosome axis is deregulated and evaluate the effects on genome integrity and the consequences from protein deregulation in meiocytes exposed to heat stress, and aberrant expression of genes encoding axis proteins in mammalian somatic cells associated with certain types of cancers.
Topics: Animals; Synaptonemal Complex; Meiosis; Chromosome Pairing; Chromatin; Neoplasms; Mammals
PubMed: 36681479
DOI: 10.1016/bs.ctdb.2022.04.008 -
Plant Biotechnology Journal Nov 2019In the last 15 years, outstanding progress has been made in understanding the function of meiotic genes in the model dicot and monocot plants Arabidopsis and rice... (Review)
Review
In the last 15 years, outstanding progress has been made in understanding the function of meiotic genes in the model dicot and monocot plants Arabidopsis and rice (Oryza sativa L.), respectively. This knowledge allowed to modulate meiotic recombination in Arabidopsis and, more recently, in rice. For instance, the overall frequency of crossovers (COs) has been stimulated 2.3- and 3.2-fold through the inactivation of the rice FANCM and RECQ4 DNA helicases, respectively, two genes involved in the repair of DNA double-strand breaks (DSBs) as noncrossovers (NCOs) of the Class II crossover pathway. Differently, the programmed induction of DSBs and COs at desired sites is currently explored by guiding the SPO11-1 topoisomerase-like transesterase, initiating meiotic recombination in all eukaryotes, to specific target regions of the rice genome. Furthermore, the inactivation of 3 meiosis-specific genes, namely PAIR1, OsREC8 and OsOSD1, in the Mitosis instead of Meiosis (MiMe) mutant turned rice meiosis into mitosis, thereby abolishing recombination and achieving the first component of apomixis, apomeiosis. The successful translation of Arabidopsis results into a crop further allowed the implementation of two breakthrough strategies that triggered parthenogenesis from the MiMe unreduced clonal egg cell and completed the second component of diplosporous apomixis. Here, we review the most recent advances in and future prospects of the manipulation of meiotic recombination in rice and potentially other major crops, all essential for global food security.
Topics: Arabidopsis; Genes, Plant; Genetic Engineering; Homologous Recombination; Meiosis; Oryza
PubMed: 31199561
DOI: 10.1111/pbi.13189 -
Cell Reports Dec 2021RNA-DNA hybrids are often associated with genome instability and also function as a cellular regulator in many biological processes. In this study, we show that...
RNA-DNA hybrids are often associated with genome instability and also function as a cellular regulator in many biological processes. In this study, we show that accumulated RNA-DNA hybrids cause multiple defects in budding yeast meiosis, including decreased sporulation efficiency and spore viability. Further analysis shows that these RNA-DNA hybrid foci colocalize with RPA/Rad51 foci on chromosomes. The efficient formation of RNA-DNA hybrid foci depends on Rad52 and ssDNA ends of meiotic DNA double-strand breaks (DSBs), and their number is correlated with DSB frequency. Interestingly, RNA-DNA hybrid foci and recombination foci show similar dynamics. The excessive accumulation of RNA-DNA hybrids around DSBs competes with Rad51/Dmc1, impairs homolog bias, and decreases crossover and noncrossover recombination. Furthermore, precocious removal of RNA-DNA hybrids by RNase H1 overexpression also impairs meiotic recombination similarly. Taken together, our results demonstrate that RNA-DNA hybrids form at ssDNA ends of DSBs to actively regulate meiotic recombination.
Topics: Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA Breaks, Single-Stranded; DNA, Fungal; DNA-Binding Proteins; Homologous Recombination; Meiosis; Nucleic Acid Conformation; Nucleic Acid Heteroduplexes; RNA, Fungal; Rad51 Recombinase; Replication Protein A; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34879269
DOI: 10.1016/j.celrep.2021.110097 -
Genes Apr 2022has been a model system for meiosis since the discovery of nondisjunction. Subsequent studies have determined that crossing over is required for chromosome segregation,... (Review)
Review
has been a model system for meiosis since the discovery of nondisjunction. Subsequent studies have determined that crossing over is required for chromosome segregation, and identified proteins required for the pairing of chromosomes, initiating meiotic recombination, producing crossover events, and building a spindle to segregate the chromosomes. With a variety of genetic and cytological tools, remains a model organism for the study of meiosis. This review focusses on meiosis in females because in male meiosis, the use of chiasmata to link homologous chromosomes has been replaced by a recombination-independent mechanism. oocytes are also a good model for mammalian meiosis because of biological similarities such as long pauses between meiotic stages and the absence of centrosomes during the meiotic divisions.
Topics: Animals; Chromosome Segregation; Chromosomes; Drosophila; Female; Male; Mammals; Meiosis; Nondisjunction, Genetic
PubMed: 35627159
DOI: 10.3390/genes13050775 -
Plant Reproduction Mar 2023Chromatin state, and dynamic loading of pro-crossover protein HEI10 at recombination intermediates shape meiotic chromosome patterning in plants. Meiosis is the basis of... (Review)
Review
Chromatin state, and dynamic loading of pro-crossover protein HEI10 at recombination intermediates shape meiotic chromosome patterning in plants. Meiosis is the basis of sexual reproduction, and its basic progression is conserved across eukaryote kingdoms. A key feature of meiosis is the formation of crossovers which result in the reciprocal exchange of segments of maternal and paternal chromosomes. This exchange generates chromosomes with new combinations of alleles, increasing the efficiency of both natural and artificial selection. Crossovers also form a physical link between homologous chromosomes at metaphase I which is critical for accurate chromosome segregation and fertility. The patterning of crossovers along the length of chromosomes is a highly regulated process, and our current understanding of its regulation forms the focus of this review. At the global scale, crossover patterning in plants is largely governed by the classically observed phenomena of crossover interference, crossover homeostasis and the obligatory crossover which regulate the total number of crossovers and their relative spacing. The molecular actors behind these phenomena have long remained obscure, but recent studies in plants implicate HEI10 and ZYP1 as key players in their coordination. In addition to these broad forces, a wealth of recent studies has highlighted how genomic and epigenomic features shape crossover formation at both chromosomal and local scales, revealing that crossovers are primarily located in open chromatin associated with gene promoters and terminators with low nucleosome occupancy.
Topics: Crossing Over, Genetic; Chromatin; Meiosis
PubMed: 35834006
DOI: 10.1007/s00497-022-00445-4 -
Proceedings of the National Academy of... Nov 2023Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged...
Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged as a regulator of DSB timing, number, and location, with a particularly important role in targeting DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including the conserved and essential DSB-promoting factor REC114, so it was hypothesized to be a modular scaffold that "anchors" other proteins together and to meiotic chromosomes. To determine whether and why the REC114 interaction is important for ANKRD31 function, we generated mice with mutations that either reduced (missense mutation) or eliminated (C-terminal truncation) the ANKRD31-REC114 interaction without diminishing contacts with other known partners. A complete lack of the ANKRD31-REC114 interaction mimicked an null, with delayed DSB formation and recombination, defects in DSB repair, and altered DSB locations including failure to target DSBs to the PARs. In contrast, when the ANKRD31-REC114 interaction was substantially but not completely disrupted, spermatocytes again showed delayed DSB formation globally, but recombination and repair were hardly affected and DSB locations were similar to control mice. The missense allele showed a dosage effect, wherein combining it with the null or C-terminal truncation allele resulted in intermediate phenotypes for DSB formation, recombination, and DSB locations. Our results show that ANKRD31 function is critically dependent on its interaction with REC114 and that defects in ANKRD31 activity correlate with the severity of the disruption of the interaction.
Topics: Animals; Male; Mice; Chromosomes; Homologous Recombination; Meiosis; Mutation; Spermatogenesis
PubMed: 37976262
DOI: 10.1073/pnas.2310951120 -
Journal of Molecular Cell Biology Sep 2022Meiosis is essential for evolution and genetic diversity in almost all sexual eukaryotic organisms. The mechanisms of meiotic recombination, such as synapsis, have been...
Meiosis is essential for evolution and genetic diversity in almost all sexual eukaryotic organisms. The mechanisms of meiotic recombination, such as synapsis, have been extensively investigated. However, it is still unclear whether signals from the cytoplasm or even from outside of the cell can regulate the meiosis process. Cilia are microtubule-based structures that protrude from the cell surface and function as signaling hubs to sense extracellular signals. Here, we reported an unexpected and critical role of cilia during meiotic recombination. During gametogenesis of zebrafish, cilia were specifically present in the prophase stages of both primary spermatocytes and primary oocytes. By developing a germ cell-specific CRISPR/Cas9 system, we demonstrated that germ cell-specific depletion of ciliary genes resulted in compromised double-strand break repair, reduced crossover formation, and increased germ cell apoptosis. Our study reveals a previously undiscovered role for cilia during meiosis and suggests that extracellular signals may regulate meiotic recombination via this particular organelle.
Topics: Animals; Male; Zebrafish; Cilia; Meiosis; Chromosome Pairing; DNA Repair
PubMed: 35981808
DOI: 10.1093/jmcb/mjac049