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Frontiers in Cell and Developmental... 2021Germ cells undergoing meiosis rely on an intricate network of surveillance mechanisms that govern the production of euploid gametes for successful sexual reproduction.... (Review)
Review
Germ cells undergoing meiosis rely on an intricate network of surveillance mechanisms that govern the production of euploid gametes for successful sexual reproduction. These surveillance mechanisms are particularly crucial during meiotic prophase, when cells execute a highly orchestrated program of chromosome morphogenesis and recombination, which must be integrated with the meiotic cell division machinery to ensure the safe execution of meiosis. Dynamic protein phosphorylation, controlled by kinases and phosphatases, has emerged as one of the main signaling routes for providing readout and regulation of chromosomal and cellular behavior throughout meiotic prophase. In this review, we discuss common principles and provide detailed examples of how these phosphorylation events are employed to ensure faithful passage of chromosomes from one generation to the next.
PubMed: 33928091
DOI: 10.3389/fcell.2021.667073 -
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 -
Sexual Development : Genetics,... 2022Meiosis is a crucial process for germ cell development. It consists of 1 round of DNA replication followed by 2 rounds of chromosome segregation, producing haploid... (Review)
Review
BACKGROUND
Meiosis is a crucial process for germ cell development. It consists of 1 round of DNA replication followed by 2 rounds of chromosome segregation, producing haploid gametes from diploid cells. During meiotic prophase, chromosomes are organized into axis-loop structures, which underlie meiosis-specific events such as meiotic recombination and homolog synapsis. Meiosis-specific cohesin plays a pivotal role in establishing higher-order chromosome architecture and regulating chromosome dynamics.
SUMMARY
Notably, sexually dimorphic properties of chromosome architecture are prominent during meiotic prophase, despite the same axial proteins being conserved between male and female. The difference in chromosome structure between the sexes gives sexual differences in the regulation of meiotic recombination and crossover distribution.
KEY MESSAGES
This review mainly focuses on the sexual differences of meiosis from the viewpoint of chromosome structure in mammals, elucidating the differences in meiotic recombination and homolog synapsis between the sexes.
PubMed: 35130542
DOI: 10.1159/000520682 -
Frontiers in Cell and Developmental... 2022Meiocytes organize higher-order chromosome structures comprising arrays of chromatin loops organized at their bases by linear axes. As meiotic prophase progresses, the... (Review)
Review
Meiocytes organize higher-order chromosome structures comprising arrays of chromatin loops organized at their bases by linear axes. As meiotic prophase progresses, the axes of homologous chromosomes align and synapse along their lengths to form ladder-like structures called synaptonemal complexes (SCs). The entire process of meiotic recombination, from initiation programmed DNA double-strand breaks (DSBs) to completion of DSB repair with crossover or non-crossover outcomes, occurs in the context of chromosome axes and SCs. These meiosis-specific chromosome structures provide specialized environments for the regulation of DSB formation and crossing over. In this review, we summarize insights into the importance of chromosome architecture in the regulation of meiotic recombination, focusing on cohesin-mediated axis formation, DSB regulation tethered loop-axis complexes, inter-homolog template bias facilitated by axial proteins, and crossover regulation in the context of the SCs. We also discuss emerging evidence that the SUMO and the ubiquitin-proteasome system function in the organization of chromosome structure and regulation of meiotic recombination.
PubMed: 36684419
DOI: 10.3389/fcell.2022.1097446 -
Nucleus (Austin, Tex.) Dec 2024Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing... (Review)
Review
Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I.
Topics: Heterochromatin; Centromere; Meiosis; Chromosome Pairing
PubMed: 38488152
DOI: 10.1080/19491034.2024.2328719 -
Clinical and Translational Medicine Jul 2022An impeccable female meiotic prophase is critical for producing a high-quality oocyte and, ultimately, a healthy newborn. SYCP3 is a key component of the synaptonemal...
BACKGROUND
An impeccable female meiotic prophase is critical for producing a high-quality oocyte and, ultimately, a healthy newborn. SYCP3 is a key component of the synaptonemal complex regulating meiotic homologous recombination. However, what regulates SYCP3 stability is unknown.
METHODS
Fertility assays, follicle counting, meiotic prophase stage (leptotene, zygotene, pachytene and diplotene) analysis and live imaging were employed to examine how FBXW24 knockout (KO) affect female fertility, follicle reserve, oocyte quality, meiotic prophase progression of female germ cells, and meiosis of oocytes. Western blot and immunostaining were used to examined the levels & signals (intensity, foci) of SYCP3 and multiple key DSB indicators & repair proteins (γH2AX, RPA2, p-CHK2, RAD51, MLH1, HORMAD1, TRIP13) after FBXW24 KO. Co-IP and immuno-EM were used to examined the interaction between FBXW24 and SYCP3; Mass spec was used to characterize the ubiquitination sites in SYCP3; In vivo & in vitro ubiquitination assays were utilized to determine the key sites in SYCP3 & FBXW24 for ubiquitination.
RESULTS
Fbxw24-knockout (KO) female mice were infertile due to massive oocyte death upon meiosis entry. Fbxw24-KO oocytes were defective due to elevated DNA double-strand breaks (DSBs) and inseparable homologous chromosomes. Fbxw24-KO germ cells showed increased SYCP3 levels, delayed prophase progression, increased DSBs, and decreased crossover foci. Next, we found that FBXW24 directly binds and ubiquitinates SYCP3 to regulate its stability. In addition, several key residues important for SYCP3 ubiquitination and FBXW24 ubiquitinating activity were characterized.
CONCLUSIONS
We proposed that FBXW24 regulates the timely degradation of SYCP3 to ensure normal crossover and DSB repair during pachytene. FBXW24-KO delayed SYCP3 degradation and DSB repair from pachytene until metaphase II (MII), ultimately causing failure in oocyte maturation, oocyte death, and infertility.
Topics: Animals; Cell Cycle Proteins; DNA-Binding Proteins; F-Box Proteins; Female; Meiosis; Mice; Prophase; Synaptonemal Complex; Ubiquitination
PubMed: 35858239
DOI: 10.1002/ctm2.891 -
Annual Review of Genomics and Human... Aug 2023In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome... (Review)
Review
In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome axes. The mammalian SC comprises at least eight largely coiled-coil proteins that interact and self-assemble to generate a long, zipper-like structure that holds homologous chromosomes in close proximity and promotes the formation of genetic crossovers and accurate meiotic chromosome segregation. In recent years, numerous mutations in human SC genes have been associated with different types of male and female infertility. Here, we integrate structural information on the human SC with mouse and human genetics to describe the molecular mechanisms by which SC mutations can result in human infertility. We outline certain themes in which different SC proteins are susceptible to different types of disease mutation and how genetic variants with seemingly minor effects on SC proteins may act as dominant-negative mutations in which the heterozygous state is pathogenic.
Topics: Male; Female; Humans; Mice; Animals; Synaptonemal Complex; Chromosome Pairing; Meiosis; Infertility; Mutation; Mammals
PubMed: 37159901
DOI: 10.1146/annurev-genom-110122-090239 -
Frontiers in Cell and Developmental... 2021One of the most fascinating aspects of meiosis is the extensive reorganization of the genome at the prophase of the first meiotic division (prophase I). The first steps... (Review)
Review
One of the most fascinating aspects of meiosis is the extensive reorganization of the genome at the prophase of the first meiotic division (prophase I). The first steps of this reorganization are observed with the establishment of an axis structure, that connects sister chromatids, from which emanate arrays of chromatin loops. This axis structure, called the axial element, consists of various proteins, such as cohesins, HORMA-domain proteins, and axial element proteins. In many organisms, axial elements are required to set the stage for efficient sister chromatid cohesion and meiotic recombination, necessary for the recognition of the homologous chromosomes. Here, we review the different actors involved in axial element formation in and in mouse. We describe the current knowledge of their localization pattern during prophase I, their functional interdependence, their role in sister chromatid cohesion, loop axis formation, homolog pairing before meiotic recombination, and recombination. We also address further challenges that need to be resolved, to fully understand the interplay between the chromosome structure and the different molecular steps that take place in early prophase I, which lead to the successful outcome of meiosis I.
PubMed: 34150782
DOI: 10.3389/fcell.2021.688878 -
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 -
Biology of Reproduction Jun 2020
Topics: Animals; Cell Cycle Checkpoints; Cell Cycle Proteins; Humans; Male; Meiosis; Meiotic Prophase I; Metaphase; SKP Cullin F-Box Protein Ligases; Spermatozoa; Ubiquitin
PubMed: 32338765
DOI: 10.1093/biolre/ioaa063