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1.
Life Sci Alliance ; 6(4)2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36650056

RESUMO

Posttranslational protein S-palmitoylation regulates the localization and function of its target proteins involved in diverse cellular processes including meiosis. In this study, we demonstrate that S-palmitoylation mediated by Erf2-Erf4 and Akr1 palmitoylacyltransferases is required at multiple meiotic stages in the fission yeast Schizosaccharomyces pombe We find that S-palmitoylation by Erf2-Erf4 is required for Ras1 localization at the cell periphery to enrich at the cell conjugation site for mating pheromone response. In the absence of Erf2 or Erf4, mutant cells are sterile. A role of Akr1 S-palmitoylating the nuclear fusion protein Tht1 to function in karyogamy is identified. We demonstrate that S-palmitoylation stabilizes and localizes Tht1 to ER, interacting with Sey1 ER fusion GTPase for proper meiotic nuclear fusion. In akr1, tht1, or sey1 mutant, meiotic cells, haploid nuclei are unfused with subsequent chromosome segregation defects. Erf2-Erf4 has an additional substrate of the spore coat protein Isp3. In the absence of Erf2, Isp3 is mislocalized from the spore coat. Together, these results highlight the versatility of the cellular processes in which protein S-palmitoylation participates.


Assuntos
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Lipoilação/fisiologia , Meiose , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo
2.
Nat Commun ; 14(1): 416, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36697412

RESUMO

The molecular causes of deteriorating oocyte quality during aging are poorly defined. Since oocyte developmental competence relies on post-transcriptional regulations, we tested whether defective mRNA translation contributes to this decline in quality. Disruption in ribosome loading on maternal transcripts is present in old oocytes. Using a candidate approach, we detect altered translation of 3'-UTR-reporters and altered poly(A) length of the endogenous mRNAs. mRNA polyadenylation depends on the cytoplasmic polyadenylation binding protein 1 (CPEB1). Cpeb1 mRNA translation and protein levels are decreased in old oocytes. This decrease causes de-repression of Ccnb1 translation in quiescent oocytes, premature CDK1 activation, and accelerated reentry into meiosis. De-repression of Ccnb1 is corrected by Cpeb1 mRNA injection in old oocytes. Oocyte-specific Cpeb1 haploinsufficiency in young oocytes recapitulates all the translation phenotypes of old oocytes. These findings demonstrate that a dysfunction in the oocyte translation program is associated with the decline in oocyte quality during aging.


Assuntos
Poliadenilação , Fatores de Poliadenilação e Clivagem de mRNA , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Oócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Meiose/genética , Biossíntese de Proteínas
3.
J Cell Biol ; 222(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36689194

RESUMO

While our understanding of the nuclear pore complex (NPC) structure is progressing spectacularly, the organizational principles of its nuclear basket remain elusive. In this issue, King et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202204039) provide new insights into the mechanisms that govern nuclear basket reorganization during meiosis.


Assuntos
Núcleo Celular , Meiose , Poro Nuclear
4.
PLoS Genet ; 19(1): e1010363, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36608115

RESUMO

The conserved two-component XMAP215/TACC modulator of microtubule stability is required in multiple animal phyla for acentrosomal spindle assembly during oocyte meiotic cell division. In C. elegans, XMAP215/zyg-9 and TACC/tac-1 mutant oocytes exhibit multiple and indistinguishable oocyte spindle assembly defects beginning early in meiosis I. To determine if these defects represent one or more early requirements with additional later and indirect consequences, or multiple temporally distinct and more direct requirements, we have used live cell imaging and fast-acting temperature-sensitive zyg-9 and tac-1 alleles to dissect their requirements at high temporal resolution. Temperature upshift and downshift experiments indicate that the ZYG-9/TAC-1 complex has multiple temporally distinct and separable requirements throughout oocyte meiotic cell division. First, we show that during prometaphase ZYG-9 and TAC-1 promote the coalescence of early pole foci into a bipolar structure, stabilizing pole foci as they grow and limiting their growth rate, with these requirements being independent of an earlier defect in microtubule organization that occurs upon nuclear envelope breakdown. Second, during metaphase, ZYG-9 and TAC-1 maintain spindle bipolarity by suppressing ectopic pole formation. Third, we show that ZYG-9 and TAC-1 also are required for spindle assembly during meiosis II, independently of their meiosis I requirements. The metaphase pole stability requirement appears to be important for maintaining chromosome congression, and we discuss how negative regulation of microtubule stability by ZYG-9/TAC-1 during oocyte meiotic cell division might account for the observed defects in spindle pole coalescence and stability.


Assuntos
Caenorhabditis elegans , Fuso Acromático , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Fuso Acromático/metabolismo , Microtúbulos/genética , Microtúbulos/metabolismo , Polos do Fuso/genética , Meiose/genética , Oócitos/metabolismo
5.
PLoS Genet ; 19(1): e1010592, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36608114

RESUMO

Meiotic recombination is a driving force for genome evolution, deeply characterized in a few model species, notably in the budding yeast Saccharomyces cerevisiae. Interestingly, Zip2, Zip3, Zip4, Spo16, Msh4, and Msh5, members of the so-called ZMM pathway that implements the interfering meiotic crossover pathway in S. cerevisiae, have been lost in Lachancea yeast species after the divergence of Lachancea kluyveri from the rest of the clade. In this context, after investigating meiosis in L. kluyveri, we determined the meiotic recombination landscape of Lachancea waltii. Attempts to generate diploid strains with fully hybrid genomes invariably resulted in strains with frequent whole-chromosome aneuploidy and multiple extended regions of loss of heterozygosity (LOH), which mechanistic origin is so far unclear. Despite the lack of multiple ZMM pro-crossover factors in L. waltii, numbers of crossovers and noncrossovers per meiosis were higher than in L. kluyveri but lower than in S. cerevisiae, for comparable genome sizes. Similar to L. kluyveri but opposite to S. cerevisiae, L. waltii exhibits an elevated frequency of zero-crossover bivalents. Lengths of gene conversion tracts for both crossovers and non-crossovers in L. waltii were comparable to those observed in S. cerevisiae and shorter than in L. kluyveri despite the lack of Mlh2, a factor limiting conversion tract size in S. cerevisiae. L. waltii recombination hotspots were not shared with either S. cerevisiae or L. kluyveri, showing that meiotic recombination hotspots can evolve at a rather limited evolutionary scale within budding yeasts. Finally, L. waltii crossover interference was reduced relative to S. cerevisiae, with interference being detected only in the 25 kb distance range. Detection of positive inference only at short distance scales in the absence of multiple ZMM factors required for interference-sensitive crossovers in other systems likely reflects interference between early recombination precursors such as DSBs.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Troca Genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/genética , Saccharomycetales/metabolismo , Meiose/genética , Proteínas MutL/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Ligação a DNA/genética , Ubiquitina-Proteína Ligases/genética
6.
Curr Top Dev Biol ; 151: 127-154, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681468

RESUMO

Inheriting the wrong number of chromosomes is one of the leading causes of infertility and birth defects in humans. However, in many organisms, individual chromosomes vary dramatically in both organization, sequence, and size. Chromosome segregation systems must be capable of accounting for these differences to reliably segregate chromosomes. During gametogenesis, meiosis ensures that all chromosomes segregate properly into gametes (i.e., egg or sperm). Interestingly, not all chromosomes exhibit the same dynamics during meiosis, which can lead to chromosome-specific behaviors and defects. This review will summarize some of the chromosome-specific meiotic events that are currently known and discuss their impact on meiotic outcomes.


Assuntos
Cromossomos , Sêmen , Humanos , Masculino , Cromossomos/genética , Meiose/genética , Gametogênese , Segregação de Cromossomos/genética
7.
Curr Top Dev Biol ; 151: 69-90, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681478

RESUMO

Sexually reproducing organisms produce haploid gametes through meiotic cell division, during which a single round of DNA replication is followed by two consecutive chromosome segregation. A series of meiosis-specific events take place during the meiotic prophase to ensure successful chromosome segregation. These events include programmed DNA double-strand break formation, chromosome movement driven by cytoplasmic forces, homologous pairing, synaptonemal complex installation, and inter-homolog crossover formation. Phase separation has emerged as a key principle controlling cellular biomolecular material organization and biological processes. Recent studies have revealed the involvements of phase separation in assembling meiotic chromosome-associated structures. Here we review and discuss how phase separation may participate in meiotic chromosome dynamics and propose that it may provide opportunities to understand the mysteries in meiotic regulations.


Assuntos
Meiose , Complexo Sinaptonêmico , Quebras de DNA de Cadeia Dupla , Segregação de Cromossomos
8.
Curr Top Dev Biol ; 151: 217-244, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681471

RESUMO

Segregation of chromosomes during meiosis, to form haploid gametes from diploid precursor cells, requires in most species formation of crossovers physically connecting homologous chromosomes. Along with sister chromatid cohesion, crossovers allow tension to be generated when chromosomes begin to segregate; tension signals that chromosome movement is proceeding properly. But crossovers too close to each other might result in less sister chromatid cohesion and tension and thus failed meiosis. Interference describes the non-random distribution of crossovers, which occur farther apart than expected from independence. We discuss both genetic and cytological methods of assaying crossover interference and models for interference, whose molecular mechanism remains to be elucidated. We note marked differences among species.


Assuntos
Cromossomos , Meiose , Meiose/genética , Segregação de Cromossomos/genética
9.
Curr Top Dev Biol ; 151: 317-344, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681475

RESUMO

Sexual reproduction and the specialized cell division it relies upon, meiosis, are biological processes that present an incredible degree of both evolutionary conservation and divergence. One clear example of this paradox is the role of the evolutionarily ancient PCH-2/HORMAD module during meiosis. On one hand, the complex, and sometimes disparate, meiotic defects observed when PCH-2 and/or the meiotic HORMADS are mutated in different model systems have prevented a straightforward characterization of their conserved functions. On the other hand, these functional variations demonstrate the impressive molecular rewiring that accompanies evolution of the meiotic processes these factors are involved in. While the defects observed in pch-2 mutants appear to vary in different systems, in this review, I argue that PCH-2 has a conserved meiotic function: to coordinate meiotic recombination with synapsis to ensure an appropriate number and distribution of crossovers. Further, given the dramatic variation in how the events of recombination and synapsis are themselves regulated in different model systems, the mechanistic differences in PCH-2 and meiotic HORMAD function make biological sense when viewed as species-specific elaborations layered onto this fundamental, conserved role.


Assuntos
Adenosina Trifosfatases , Meiose , Adenosina Trifosfatases/genética , Meiose/genética , Pareamento Cromossômico
10.
Curr Top Dev Biol ; 151: 155-190, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681469

RESUMO

Crossover events during recombination in meiosis are essential for generating genetic diversity as well as crucial to allow accurate chromosomal segregation between homologous chromosomes. Spatial control for the distribution of crossover events along the chromosomes is largely a tightly regulated process and involves many facets such as interference, repression as well as assurance, to make sure that not too many or too few crossovers are generated. Repression of crossover events at the centromeres is a highly conserved process across all species tested. Failure to inhibit such recombination events can result in chromosomal mis-segregation during meiosis resulting in aneuploid gametes that are responsible for infertility or developmental disorders such as Down's syndrome and other trisomies in humans. In the past few decades, studies to understand the molecular mechanisms behind this repression have shown the involvement of a multitude of factors ranging from the centromere-specific proteins such as the kinetochore to the flanking pericentric heterochromatin as well as DNA double-strand break repair pathways. In this chapter, we review the different mechanisms of pericentric repression mechanisms known till date as well as highlight the importance of understanding this regulation in the context of chromosomal segregation defects. We also discuss the clinical implications of dysregulation of this process, especially in human reproductive health and genetic diseases.


Assuntos
Centrômero , Quebras de DNA de Cadeia Dupla , Humanos , Centrômero/genética , Meiose/genética
11.
Curr Top Dev Biol ; 151: 27-42, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681473

RESUMO

Recent discoveries have advanced our understanding of recombination initiation beyond the placement of double-stranded DNA breaks (DSBs) from germline replication timing to the dynamic reorganization of chromatin, and defined critical players of recombination initiation. This article focuses on recombination initiation in mammals utilizing the PRDM9 protein to orchestrate crucial stages of meiotic recombination initiation by interacting with the local DNA environment and several protein complexes. The Pioneer Complex with the SNF2-type chromatin remodeling enzyme HELLS, exposes PRDM9-bound DNA. At the same time, a Compass-Complex containing EWSR1, CXXC1, CDYL, EHMT2 and PRDM9 facilitates the association of putative hotspot sites in DNA loops with the chromosomal axis where DSB-promoting complexes are located, and DSBs are catalyzed by the SPO11/TOPOVIBL complex. Finally, homology search is facilitated at PRDM9-directed sites by ANKRD31. The Reader-Writer system consists of PRDM9 writing characteristic histone methylation signatures, which are read by ZCWPW1, promoting efficient homology engagement.


Assuntos
Cromatina , DNA , Animais , DNA/metabolismo , Cromossomos , Recombinação Homóloga , Quebras de DNA de Cadeia Dupla , Meiose/genética , Mamíferos/genética
12.
Curr Top Dev Biol ; 151: 91-126, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681479

RESUMO

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.


Assuntos
Neoplasias , Complexo Sinaptonêmico , Animais , Meiose/genética , Pareamento Cromossômico , Cromatina/genética , Neoplasias/genética , Mamíferos/genética
13.
Curr Top Dev Biol ; 151: 1-26, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681467

RESUMO

Meiosis is critical for germ cell development in multicellular organisms. Initiation of meiosis coincides with pre-meiotic S phase, which is followed by meiotic prophase, a prolonged G2 phase that ensures numerous meiosis-specific chromosome events. Meiotic prophase is accompanied by robust alterations of gene expression. In mouse germ cells, MEIOSIN and STRA8 direct cell cycle switch from mitosis to meiosis. MEIOSIN and STRA8 coordinate meiotic initiation with cell cycle, by activating the meiotic genes to have meiotic prophase program installed at S phase. This review mainly focuses on the mechanism of meiotic initiation in mouse germ cells from the viewpoint of the transcription of meiotic genes. Furthermore, signaling pathways that regulate meiotic initiation will be discussed in the context of germ cell development, pointing out the sexual differences in the mode of meiotic initiation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Meiose , Camundongos , Animais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Mitose , Transdução de Sinais , Células Germinativas
14.
Curr Top Dev Biol ; 151: 281-315, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681474

RESUMO

Chromosomal transactions such as replication, recombination and segregation are monitored by cell cycle checkpoint cascades. These checkpoints ensure the proper execution of processes that are needed for faithful genome inheritance from one cell to the next, and across generations. In meiotic prophase, a specialized checkpoint monitors defining events of meiosis: programmed DNA break formation, followed by dedicated repair through recombination based on interhomolog (IH) crossovers. This checkpoint shares molecular characteristics with canonical DNA damage checkpoints active during somatic cell cycles. However, idiosyncratic requirements of meiotic prophase have introduced unique features in this signaling cascade. In this review, we discuss the unique features of the meiotic prophase checkpoint. While being related to canonical DNA damage checkpoint cascades, the meiotic prophase checkpoint also shows similarities with the spindle assembly checkpoint (SAC) that guards chromosome segregation. We highlight these emerging similarities in the signaling logic of the checkpoints that govern meiotic prophase and chromosome segregation, and how thinking of these similarities can help us better understand meiotic prophase control. We also discuss work showing that, when aberrantly expressed, components of the meiotic prophase checkpoint might alter DNA repair fidelity and chromosome segregation in cancer cells. Considering checkpoint function in light of demands imposed by the special characteristics of meiotic prophase helps us understand checkpoint integration into the meiotic cell cycle machinery.


Assuntos
Quebras de DNA de Cadeia Dupla , Meiose , Prófase , Reparo do DNA , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo
15.
Curr Top Dev Biol ; 151: 345-369, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681476

RESUMO

Successful in vitro spermatogenesis would generate functional haploid spermatids, and thus, form the basis for novel approaches to treat patients with impaired spermatogenesis or develop alternative strategies for male fertility preservation. Several culture strategies, including cell cultures using various stem cells and ex vivo cultures of testicular tissue, have been investigated to recapitulate spermatogenesis in vitro. Although some studies have described complete meiosis and subsequent generation of functional spermatids, key meiotic events, such as chromosome synapsis and homologous recombination required for successful meiosis and faithful in vitro-derived gametes, are often not reported. To guarantee the generation of in vitro-formed spermatids without persistent DNA double-strand breaks (DSBs) and chromosomal aberrations, criteria to evaluate whether all meiotic events are completely executed in vitro need to be established. In vivo, these meiotic events are strictly monitored by meiotic checkpoints that eliminate aberrant spermatocytes. To establish criteria to evaluate in vitro meiosis, we review the meiotic events and checkpoints that have been investigated by previous in vitro spermatogenesis studies. We found that, although major meiotic events such as initiation of DSBs and recombination, complete chromosome synapsis, and XY-body formation can be achieved in vitro, crossover formation, chiasmata frequency, and checkpoint mechanisms have been mostly ignored. In addition, complete spermiogenesis, during which round spermatids differentiate into elongated spermatids, has not been achieved in vitro by various cell culture strategies. Finally, we discuss the implications of meiotic checkpoints for in vitro spermatogenesis protocols and future clinical use.


Assuntos
Espermátides , Espermatogênese , Humanos , Masculino , Espermatogênese/genética , Espermatócitos , Meiose , Cromossomos Sexuais
16.
Curr Top Dev Biol ; 151: 245-279, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681472

RESUMO

Meiosis is characterized by highly regulated transitions in gene expression that require diverse mechanisms of gene regulation. For example, in male mammals, transcription undergoes a global shut-down in early prophase I of meiosis, followed by increasing transcriptional activity into pachynema. Later, as spermiogenesis proceeds, the histones bound to DNA are replaced with transition proteins, which are themselves replaced with protamines, resulting in a highly condensed nucleus with repressed transcriptional activity. In addition, two specialized gene silencing events take place during prophase I: meiotic silencing of unsynapsed chromatin (MSUC), and the sex chromatin specific mechanism, meiotic sex chromosome inactivation (MSCI). Notably, conserved roles for the RNA binding protein (RBP) machinery that functions with small non-coding RNAs have been described as participating in these meiosis-specific mechanisms, suggesting that RNA-mediated gene regulation is critical for fertility in many species. Here, we review roles of small RNAs and their associated RBPs in meiosis-related processes such as centromere function, silencing of unpaired chromatin and meiotic recombination. We will discuss the emerging evidence of non-canonical functions of these components in meiosis.


Assuntos
Cromatina , Cromossomos Sexuais , Animais , Masculino , Cromossomos Sexuais/genética , Cromatina/genética , Meiose/genética , Histonas/genética , RNA , Mamíferos/genética , Mamíferos/metabolismo
17.
Curr Top Dev Biol ; 151: 43-68, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681477

RESUMO

Meiosis increases genetic diversity in offspring by generating genetically unique haploid gametes with reshuffled chromosomes. This process requires a specialized set of meiotic proteins, which facilitate chromosome recombination and segregation. However, re-expression of meiotic proteins in mitosis can have catastrophic oncogenic consequences and aberrant expression of meiotic proteins is a common occurrence in human tumors. Mechanistically, re-activation of meiotic genes in cancer promotes oncogenesis likely because cancers-conversely to healthy mitosis-are fueled by genetic instability which promotes tumor evolution, and evasion of immune response and treatment pressure. In this review, we explore similarities between meiotic and cancer cells with a particular focus on the oncogenic activation of meiotic genes in cancer. We emphasize the role of histones and their modifications, DNA methylation, genome organization, R-loops and the availability of distal enhancers.


Assuntos
Meiose , Neoplasias , Humanos , Meiose/genética , Cromossomos , Histonas/genética , Expressão Gênica , Neoplasias/genética
18.
Curr Top Dev Biol ; 151: 191-215, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681470

RESUMO

Successful meiosis I requires that homologous chromosomes be correctly linked before they are segregated. In most organisms this physical linkage is achieved through the generation of crossovers between the homologs. Meiotic recombination co-opts and modifies the canonical homologous recombination pathway to successfully generate crossovers One of the central components of this pathway are a number of conserved DNA helicases. Helicases couple nucleic acid binding to nucleotide hydrolysis and use this activity to modify DNA or protein-DNA substrates. During meiosis I it is necessary for the cell to modulate the canonical DNA repair pathways in order to facilitate the generation of interhomolog crossovers. Many of these meiotic modulations take place in pathways involving DNA helicases, or with a meiosis specific helicase. This short review explores what is currently understood about these helicases, their interaction partners, and the role of regulatory modifications during meiosis I. We focus in particular on the molecular structure and mechanisms of these helicases.


Assuntos
Reparo do DNA , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Recombinação Homóloga , Meiose
19.
J Cell Biol ; 222(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36622328

RESUMO

Gametogenesis requires packaging of the cellular components needed for the next generation. In budding yeast, this process includes degradation of many mitotically stable proteins, followed by their resynthesis. Here, we show that one such case-Superoxide dismutase 1 (Sod1), a protein that commonly aggregates in human ALS patients-is regulated by an integrated set of events, beginning with the formation of pre-meiotic Sod1 aggregates. This is followed by degradation of a subset of the prior Sod1 pool and clearance of Sod1 aggregates. As degradation progresses, Sod1 protein production is transiently blocked during mid-meiotic stages by transcription of an extended and poorly translated SOD1 mRNA isoform, SOD1LUTI. Expression of SOD1LUTI is induced by the Unfolded Protein Response, and it acts to repress canonical SOD1 mRNA expression. SOD1LUTI is no longer expressed following the meiotic divisions, enabling a resurgence of canonical mRNA and synthesis of new Sod1 protein such that gametes inherit a full complement of Sod1 protein. Failure to aggregate and degrade Sod1 results in reduced gamete fitness in the presence of oxidants, highlighting the importance of this regulation. Investigation of Sod1 during yeast gametogenesis, an unusual cellular context in which Sod1 levels are tightly regulated, could shed light on conserved aspects of its aggregation and degradation, with relevance to understanding Sod1's role in human disease.


Assuntos
Agregados Proteicos , Proteínas de Saccharomyces cerevisiae , Superóxido Dismutase-1 , Humanos , Esclerose Amiotrófica Lateral/metabolismo , Mutação , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Saccharomyces cerevisiae , Resposta a Proteínas não Dobradas , Meiose
20.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674642

RESUMO

P21-activated kinase 1 (PAK1), as a member of the PAK family, has been implicated in various functions during somatic mitosis; however, less is known about its role during oocyte meiosis. Herein, we highlight the indispensable role of PAK1 in regulating spindle assembly and cell cycle progression during the first meiotic division of porcine oocytes. First, we found that the activated PAK1 expressed dynamically, and its subcellular localization was tightly associated with the spindle dynamics during meiosis in porcine oocytes. Specific inhibition of PAK1 activity by inhibitor targeting PAK1 activation-3 (IPA-3) led to impaired extrusion of the first polar body (PB1); with most of the IPA-3-treated oocytes arrested at germinal vesicle breakdown (GVBD) and subjected to failure of bipolar spindle formation. However, the adverse effects caused by IPA-3 on oocytes could be restored by reducing disulfide bonds between PAK1 and IPA-3 with dithiothreitol (DTT) treatment. Furthermore, the co-immunoprecipitation assay revealed that PAK1 interacted directly with Aurora A and transforming acidic coiled coil 3 (TACC3), providing an additional explanation for the similar localization of Aurora A and activated PAK1. Additionally, inhibiting the activity of PAK1 decreased the expression of p-Aurora A and p-TACC3; however, the reduced activity of Aurora A and TACC3 could be restored by DTT. In conclusion, PAK1 plays a crucial role in the proper assembly of the spindle during the first meiotic division of porcine oocytes, and the regulation of PAK1 is associated with its effects on p-Aurora A and p-TACC3 expression.


Assuntos
Fuso Acromático , Quinases Ativadas por p21 , Suínos , Animais , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Fuso Acromático/metabolismo , Oócitos , Proteínas de Ciclo Celular/metabolismo , Meiose
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