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《Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms》2022,1865(5):194844
Meiotic recombination is a driver of evolution, and aberrant recombination is a major contributor to aneuploidy in mammals. Mechanism of recombination remains elusive yet. Here, we present a computational analysis to explore recombination-related dynamics of chromatin accessibility in mouse primordial germ cells (PGCs). Our data reveals that: (1) recombination hotspots which get accessible at meiosis-specific DNase I-hypersensitive sites (DHSs) only when PGCs enter meiosis are located preferentially in intronic and distal intergenic regions; (2) stable DHSs maintained stably across PGC differentiation are enriched by CTCF motifs and CTCF binding and mediate chromatin loop formation; (3) compared with the specific DHSs aroused at meiotic stage, stable DHSs are largely encoded in DNA sequence and also enriched by epigenetic marks; (4) PRDM9 is likely to target nucleosome-occupied hotspot regions and remodels local chromatin structure to make them accessible for recombination machinery; and (5) cells undergoing meiotic recombination are deficient in TAD structure and chromatin loop arrays are organized regularly along the axis formed between homologous chromosomes. Taken together, by analyzing DHS-related DNA features, epigenetic marks and 3D genome structure, we revealed some specific roles of chromatin accessibility in recombination, which would expand our understanding of recombination mechanism. 相似文献
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Ayelet Arbel‐Eden Giora Simchen 《BioEssays : news and reviews in molecular, cellular and developmental biology》2019,41(4)
Diploid germ cells produce haploid gametes through meiosis, a unique type of cell division. Independent reassortment of parental chromosomes and their recombination leads to ample genetic variability among the gametes. Importantly, new mutations also occur during meiosis, at frequencies much higher than during the mitotic cell cycles. These meiotic mutations are associated with genetic recombination and depend on double‐strand breaks (DSBs) that initiate crossing over. Indeed, sequence variation among related strains is greater around recombination hotspots than elsewhere in the genome, presumably resulting from recombination‐associated mutations. Significantly, enhanced mutagenicity in meiosis may lead to faster divergence during evolution, as germ‐line mutations are the ones that are transmitted to the progeny and thus have an evolutionary impact. The molecular basis for mutagenicity in meiosis may be related to the repair of meiotic DSBs by polymerases, or to the exposure of single‐strand DNA to mutagenic agents during its repair. 相似文献
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In meiosis of human males DNA is packaged along pachytene chromosomes about 20 time more compactly than in meiosis of yeast. Nevertheless, a human-derived yeast artificial chromosome (YAC) shows the same degree of compaction of DNA as endogenous chromosomes in meiotic prophase nuclei of yeast. This suggests that in yeast meiosis, human and yeast DNA adopt a similar organization of chromatin along the pachytene chromosome cores. Therefore meiotic chromatin organization does not seem to be an inherent chromosomal property but is governed by the host-specific cellular environment. We suggest that there is a correlation between the less dense DNA packaging and the increased rate of recombination that has been reported for human-derived YACs as compared with human DNA in its natural environment. 相似文献
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Involvement of Sir2/4 in silencing of DNA breakage and recombination on mouse YACs during yeast meiosis
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Klieger Y Yizhar O Zenvirth D Shtepel-Milman N Snoek M Simchen G 《Molecular biology of the cell》2005,16(3):1449-1455
Yeast artificial chromosomes (YACs) that contain human DNA backbone undergo DNA double-strand breaks (DSBs) and recombination during yeast meiosis at rates similar to the yeast native chromosomes. Surprisingly, YACs containing DNA covering a recombination hot spot in the mouse major histocompatibility complex class III region do not show meiotic DSBs and undergo meiotic recombination at reduced levels. Moreover, segregation of these YACs during meiosis is seriously compromised. In meiotic yeast cells carrying the mutations sir2 or sir4, but not sir3, these YACs show DSBs, suggesting that a unique chromatin structure of the YACs, involving Sir2 and Sir4, protects the YACs from the meiotic recombination machinery. We speculate that the paucity of DSBs and recombination events on these YACs during yeast meiosis may reflect the refractory nature of the corresponding region in the mouse genome. 相似文献
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Changes in chromatin structure at recombination initiation sites during yeast meiosis. 总被引:33,自引:6,他引:27
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Transient double-strand breaks (DSBs) occur during Saccharomyces cerevisiae meiosis at recombination hot spots and are thought to initiate most, if not all, homologous recombination between chromosomes. To uncover the regulatory mechanisms active in DSB formation, we have monitored the change in local chromatin structure at the ARG4 and CYS3 recombination hot spots over the course of meiosis. Micrococcal nuclease (MNase) digestion of isolated meiotic chromatin followed by indirect end-labeling revealed that the DSB sites in both loci are hypersensitive to MNase and that their sensitivity increases 2- to 4-fold prior to the appearance of meiotic DSBs and recombination products. Other sensitive sites are not significantly altered. The study of hyper- and hypo-recombinogenic constructs at the ARG4 locus, also revealed that the MNase sensitivity at the DSB site correlates with both the extent of DSBs and the rate of gene conversion. These results suggest that the local chromatin structure and its modification in early meiosis play an important role in the positioning and frequency of meiotic DSBs, leading to meiotic recombination. 相似文献
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VMA1-derived endonuclease (VDE), a homing endonuclease in Saccharomyces cerevisiae, is encoded by the mobile intein-coding sequence within the nuclear VMA1 gene. VDE recognizes and cleaves DNA at the 31-bp VDE recognition sequence (VRS) in the VMA1 gene lacking the intein-coding sequence during meiosis to insert a copy of the intein-coding sequence at the cleaved site. The mechanism underlying the meiosis specificity of VMA1 intein-coding sequence homing remains unclear. We studied various factors that might influence the cleavage activity in vivo and found that VDE binding to the VRS can be detected only when DNA cleavage by VDE takes place, implying that meiosis-specific DNA cleavage is regulated by the accessibility of VDE to its target site. As a possible candidate for the determinant of this accessibility, we analyzed chromatin structure around the VRS and revealed that local chromatin structure near the VRS is altered during meiosis. Although the meiotic chromatin alteration exhibits correlations with DNA binding and cleavage by VDE at the VMA1 locus, such a chromatin alteration is not necessarily observed when the VRS is embedded in ectopic gene loci. This suggests that nucleosome positioning or occupancy around the VRS by itself is not the sole mechanism for the regulation of meiosis-specific DNA cleavage by VDE and that other mechanisms are involved in the regulation. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(6):780-783
The nucleosome, composed of an octamer of highly conserved histone proteins and associated DNA, is the fundamental unit of eukaryotic chromatin. How arrays of nucleosomes are folded into higher-order structures, and how the dynamics of such compaction are regulated, are questions that remain largely unanswered. Our recent studies demonstrated that phosphorylation of histone H2B is necessary to induce cell death that exhibits phenotypic hallmarks of apoptosis including DNA fragmentation and chromatin condensation in yeast (serine 10)1 and in mammalian cells (serine 14).2 In this article, we extend these findings by uncovering a role for H2B phosphorylation at serine 10 (Ser10) in another biological event that is associated with dramatic alterations in higher-order chromatin structure, meiosis. Our data show strong staining, indicative of H2B (Ser10) phosphorylation, during the pachytene stage of yeast meiotic prophase. These data broaden the use of this phosphorylation mark in chromatin remodeling that closely correlates with chromatin compaction. How phosphorylation marks are translated into meaningful downstream events during processes as diverse as apoptosis and meiosis remains a challenge for future studies. 相似文献
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Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous chromosomes pair and undergo DNA double strand breaks generated by the Spo11 endonuclease. These breaks can be repaired as crossovers that result in reciprocal exchange between chromosomes. The frequency of recombination along chromosomes is highly variable, for example, crossovers are rarely observed in heterochromatin and the centromeric regions. Recent work in plants has shown that crossover hotspots occur in gene promoters and are associated with specific chromatin modifications, including H2 A.Z. Meiotic chromosomes are also organized in loop-base arrays connected to an underlying chromosome axis, which likely interacts with chromatin to organize patterns of recombination.Therefore, epigenetic information exerts a major influence on patterns of meiotic recombination along chromosomes, genetic variation within populations and evolution of plant genomes. 相似文献
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Meiotic recombination in most mammals requires recombination hotspot activation through the action of the histone 3 Lys-4 and Lys-36 methyltransferase PRDM9 to ensure successful double-strand-break initiation and repair. Here we show that EWSR1, a protein whose role in meiosis was not previously clarified in detail, binds to both PRDM9 and pREC8, a phosphorylated meiosis-specific cohesin, in male meiotic cells. We created a Ewsr1 conditional knockout mouse model to deplete EWSR1 before the onset of meiosis and found that absence of EWSR1 causes meiotic arrest with decreased histone trimethylation at meiotic hotspots, impaired DNA double-strand-break repair, and reduced crossover number. Our results demonstrate that EWSR1 is essential for promoting PRDM9-dependent histone methylation and normal meiotic progress, possibly by facilitating the linking between PRDM9-bound hotspots and the nascent chromosome axis through its component cohesin pREC8. 相似文献
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Higgins JD Ferdous M Osman K Franklin FC 《The Plant journal : for cell and molecular biology》2011,65(3):492-502
RecQ helicases are a conserved group of proteins with a role in the maintenance of genome integrity. In Saccharomyces cerevisiae (budding yeast), meiotic recombination is increased in the absence of the RecQ helicase Sgs1. Here we investigated the potential meiotic role of the Sgs1 homologue AtRECQ4A and the closely related AtRECQ4B. Both proteins have been shown to function during recombination in somatic cells, but so far their meiotic role has not been investigated. Both AtRECQ4A and AtRECQ4B were expressed in reproductive tissues. Although immunolocalization studies showed that AtRECQ4A associates with recombination intermediates, we found no evidence that its loss or that of AtRECQ4B had a significant effect on meiotic cross-overs, suggesting functional redundancy with other RECQ family members. Nevertheless, pollen viability decreased in Atrecq4A, resulting in a reduction in fertility, although this was not the case in Atrecq4B. Cytological analysis revealed chromatin bridges between the telomeres of non-homologous chromosomes in Atrecq4A at metaphase I, in some instances accompanied by chromosome fragmentation at anaphase I. The bridges required telomeric repeats and were dependent on meiotic recombination. Immunolocalization confirmed the association of AtRECQ4A with the telomeres during prophase I, which we propose enables dissolution of recombination-dependent telomeric associations. Thus, this study has identified a hitherto unknown role for a member of the RECQ helicase family during meiosis that contributes to the maintenance of chromosome integrity. As telomere structure is generally conserved, it seems likely that these associations may arise during meiosis in other species, where they must also be removed. 相似文献
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Homologous recombination is increased during meiosis between DNA sequences at the same chromosomal position (allelic recombination) and at different chromosomal positions (ectopic recombination). Recombination hotspots are important elements in controlling meiotic allelic recombination. We have used artificially dispersed copies of the ade6 gene in Schizosaccharomyces pombe to study hotspot activity in meiotic ectopic recombination. Ectopic recombination was reduced 10-1000-fold relative to allelic recombination, and was similar to the low frequency of ectopic recombination between naturally repeated sequences in S. pombe. The M26 hotspot was active in ectopic recombination in some, but not all, integration sites, with the same pattern of activity and inactivity in ectopic and allelic recombination. Crossing over in ectopic recombination, resulting in chromosomal rearrangements, was associated with 35-60% of recombination events and was stimulated 12-fold by M26. These results suggest overlap in the mechanisms of ectopic and allelic recombination and indicate that hotspots can stimulate chromosomal rearrangements. 相似文献
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Meiotic cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion
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The cohesin complex is essential for mitosis and meiosis. The specific meiotic roles of individual cohesin proteins are incompletely understood. We report in vivo functions of the only meiosis‐specific STAG component of cohesin, STAG3. Newly generated STAG3‐deficient mice of both sexes are sterile with meiotic arrest. In these mice, meiotic chromosome architecture is severely disrupted as no bona fide axial elements (AE) form and homologous chromosomes do not synapse. Axial element protein SYCP3 forms dot‐like structures, many partially overlapping with centromeres. Asynapsis marker HORMAD1 is diffusely distributed throughout the chromatin, and SYCP1, which normally marks synapsed axes, is largely absent. Centromeric and telomeric sister chromatid cohesion are impaired. Centromere and telomere clustering occurs in the absence of STAG3, and telomere structure is not severely affected. Other cohesin proteins are present, localize throughout the STAG3‐devoid chromatin, and form complexes with cohesin SMC1β. No other deficiency in a single meiosis‐specific cohesin causes a phenotype as drastic as STAG3 deficiency. STAG3 emerges as the key STAG cohesin involved in major functions of meiotic cohesin. 相似文献
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RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. 总被引:8,自引:0,他引:8
The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. The precise immunolocalization of these two proteins on the meiotic chromosomes of plants and animals has been complicated by their high degree of identity at the amino acid level. With antibodies that have been immunodepleted of cross-reactive epitopes, we demonstrate that RAD51 and DMC1 have identical distribution patterns in extracts of mouse spermatocytes in successive prophase I stages, suggesting coordinate functionality. Immunofluorescence and immunoelectron microscopy with these antibodies demonstrate colocalization of the two proteins on the meiotic chromosome cores at early prophase I. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. 相似文献
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The DIF1 gene of Arabidopsis is required for meiotic chromosome segregation and belongs to the REC8/RAD21 cohesin gene family 总被引:5,自引:0,他引:5
Anuj M. Bhatt Clare Lister Tania Page Paul Fransz Kim Findlay Gareth H. Jones Hugh G. Dickinson Caroline Dean 《The Plant journal : for cell and molecular biology》1999,19(4):463-472
Cohesins are a group of conserved proteins responsible for cohesion between replicated sister chromatids during mitosis and meiosis and which are implicated in double-strand break repair and meiotic recombination. We describe here the identification and characterisation of an Arabidopsis gene - DETERMINATE, INFERTILE1 (DIF1), which is a homolog of the Schizosaccharomyces pombe REC8/RAD21 cohesin genes, and is essential for meiotic chromosome segregation. Five independent alleles of the DIF1 gene were isolated by transposon mutagenesis, and the mutants show complete male and female sterility. Pollen mother cells (PMCs) of dif1 mutants show multiple meiotic defects which are represented by univalent chromosomes and chromosome fragmentation at metaphase I, and acentric fragments and chromatin bridges in meiosis I and II. Consequently, chromosome segregation is strongly affected, resulting in meiotic products of uneven size, shape and of variable ploidy. The similarities in phenotype, and the sequence homology between DIF1 and the REC8/RAD21 cohesins suggests that cohesin function is largely conserved between eukaryotes and highlights the essential role cohesins play in plant meiosis. 相似文献
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Chromatin structure and function are for a large part determined by the six members of the structural maintenance of chromosomes (SMC) protein family, which form three heterodimeric complexes: Smc1/3 (cohesin), Smc2/4 (condensin) and Smc5/6. Each complex has distinct and important roles in chromatin dynamics, gene expression and differentiation. In yeast and Drosophila, Smc6 is involved in recombinational repair, restarting collapsed replication forks and prevention of recombination in repetitive sequences such as rDNA and pericentromeric heterochromatin. Although such DNA damage control mechanisms, as well as highly dynamic changes in chromatin composition and function, are essential for gametogenesis, knowledge on Smc6 function in mammalian systems is limited. We therefore have investigated the role of Smc6 during mammalian spermatogonial differentiation, meiosis and subsequent spermiogenesis. We found that, during mouse spermatogenesis, Smc6 functions as part of meiotic pericentromeric heterochromatin domains that are initiated when differentiating spermatogonia become irreversibly committed toward meiosis. To our knowledge, we are the first to provide insight into how commitment toward meiosis alters chromatin structure and dynamics, thereby setting apart differentiating spermatogonia from the undifferentiated spermatogonia, including the spermatogonial stem cells. Interestingly, Smc6 is not essential for spermatogonial mitosis, whereas Smc6-negative meiotic cells appear unable to finish their first meiotic division. Importantly, during meiosis, we find that DNA repair or recombination sites, marked by γH2AX or Rad51 respectively, do not co-localize with the pericentromeric heterochromatin domains where Smc6 is located. Considering the repetitive nature of these domains and that Smc6 has been previously shown to prevent recombination in repetitive sequences, we hypothesize that Smc6 has a role in the prevention of aberrant recombination events between pericentromeric regions during the first meiotic prophase that would otherwise cause chromosomal aberrations leading to apoptosis, meiotic arrest or aneuploidies. 相似文献