Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phosphorylation of high-mobility group protein A2 by Nek2 kinase during the first meiotic division in mouse spermatocytes.

ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

SUBMITTER: Di Agostino S

PROVIDER: S-EPMC363112 | biostudies-other | 2004 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

A Mutation in <i>Mtap2</i> Is Associated with Arrest of Mammalian Spermatocytes before the First Meiotic Division.

Project description:In spite of evolutionary conservation of meiosis, many of the genes that control mammalian meiosis are still unknown. We report here that the ENU-induced repro4 mutation, identified in a screen to uncover genes that control mouse meiosis, causes failure of spermatocytes to exit meiotic prophase I via the G2/MI transition. Major events of meiotic prophase I occurred normally in affected spermatocytes and known regulators of the meiotic G2/MI transition were present and functional. Deep sequencing of mutant DNA revealed a mutation located in an intron of Mtap2 gene, encoding microtubule-associated protein 2, and levels of Mtap2 transcript were reduced in mutant testes. This evidence implicates MTAP2 as required directly or indirectly for completion of meiosis and normal spermatogenesis in mammals.

| S-EPMC3909985 | biostudies-literature

Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes.

Project description:Meiosis relies on the SPO11 endonuclease to generate the recombinogenic DNA double strand breaks (DSBs) required for homologous chromosome synapsis and segregation. The number of meiotic DSBs needs to be sufficient to allow chromosomes to search for and find their homologs, but not excessive to the point of causing genome instability. Here we report that the mammal-specific gene Tex19.1 promotes Spo11-dependent recombination in mouse spermatocytes. We show that the chromosome asynapsis previously reported in Tex19.1-/- spermatocytes is preceded by reduced numbers of recombination foci in leptotene and zygotene. Tex19.1 is required for normal levels of early Spo11-dependent recombination foci during leptotene, but not for upstream events such as MEI4 foci formation or accumulation of H3K4me3 at recombination hotspots. Furthermore, we show that mice carrying mutations in Ubr2, which encodes an E3 ubiquitin ligase that interacts with TEX19.1, phenocopy the Tex19.1-/- recombination defects. These data suggest that Tex19.1 and Ubr2 are required for mouse spermatocytes to accumulate sufficient Spo11-dependent recombination to ensure that the homology search is consistently successful, and reveal a hitherto unknown genetic pathway promoting meiotic recombination in mammals.

| S-EPMC5533463 | biostudies-literature

APCcdh1 activity in mouse oocytes prevents entry into the first meiotic division.

Project description:Fully grown mammalian oocytes maintain a prophase I germinal-vesicle stage arrest in the ovary for extended periods before a luteinizing hormone surge induces entry into the first meiotic division. Cdh1 is an activator of the anaphase-promoting complex (APC) and APCcdh1 is normally restricted to late M to early G1 phases of the cell cycle. Here, we find that APCcdh1 is active in mouse oocytes and is necessary to maintain prophase arrest.

| S-EPMC2435241 | biostudies-other

Cross-talk between sumoylation and phosphorylation in mouse spermatocytes.

Project description:The meiotic G2/M1 transition is mostly regulated by posttranslational modifications, however, the cross-talk between different posttranslational modifications is not well-understood, especially in spermatocytes. Sumoylation has emerged as a critical regulatory event in several developmental processes, including reproduction. In mouse oocytes, inhibition of sumoylation caused various meiotic defects and led to aneuploidy. However, the role of sumoylation in male reproduction has only begun to be elucidated. Given the important role of several SUMO targets (including kinases) in meiosis, in this study, the role of sumoylation was addressed by monitoring the G2/M1 transition in pachytene spermatocytes in vitro upon inhibition of sumoylation. Furthermore, to better understand the cross-talk between sumoylation and phosphorylation, the activity of several kinases implicated in meiotic progression was also assessed upon down-regulation of sumoylation. The results of the analysis demonstrate that inhibition of sumoylation with ginkgolic acid (GA) arrests the G2/M1 transition in mouse spermatocytes preventing chromosome condensation and disassembling of the synaptonemal complex. Our results revealed that the activity of PLK1 and the Aurora kinases increased during the G2/M1 meiotic transition, but was negatively regulated by the inhibition of sumoylation. In the same experiment, the activity of c-Abl, the ERKs, and AKT were not affected or increased after GA treatment. Both the AURKs and PLK1 appear to be "at the right place, at the right time" to at least, in part, explain the meiotic arrest obtained in the spermatocyte culture.

| S-EPMC5497584 | biostudies-literature

Defects in meiotic recombination delay progression through pachytene in Tex19.1-/- mouse spermatocytes.

Project description:Recombination, synapsis, chromosome segregation and gene expression are co-ordinately regulated during meiosis to ensure successful execution of this specialised cell division. Studies with multiple mutant mouse lines have shown that mouse spermatocytes possess quality control checkpoints that eliminate cells with persistent defects in chromosome synapsis. In addition, studies on Trip13mod/mod mice suggest that pachytene spermatocytes that successfully complete chromosome synapsis can undergo meiotic arrest in response to defects in recombination. Here, we present additional support for a meiotic recombination-dependent checkpoint using a different mutant mouse line, Tex19.1-/-. The appearance of early recombination foci is delayed in Tex19.1-/- spermatocytes during leptotene/zygotene, but some Tex19.1-/- spermatocytes still successfully synapse their chromosomes and we show that these spermatocytes are enriched for early recombination foci. Furthermore, we show that patterns of axis elongation, chromatin modifications and histone H1t expression are also all co-ordinately skewed towards earlier substages of pachytene in these autosomally synapsed Tex19.1-/- spermatocytes. We also show that this skew towards earlier pachytene substages occurs in the absence of elevated spermatocyte death in the population, that spermatocytes with features of early pachytene are present in late stage Tex19.1-/- testis tubules and that the delay in histone H1t expression in response to loss of Tex19.1 does not occur in a Spo11 mutant background. Taken together, these data suggest that a recombination-dependent checkpoint may be able to modulate pachytene progression in mouse spermatocytes to accommodate some types of recombination defect.

| S-EPMC6208735 | biostudies-literature

Dynamics of DOT1L localization and H3K79 methylation during meiotic prophase I in mouse spermatocytes.

Project description:During meiotic prophase I, interactions between maternal and paternal chromosomes, under checkpoint surveillance, establish connections between homologs that promote their accurate distribution to meiotic progeny. In human, faulty meiosis causes aneuploidy resulting in miscarriages and genetic diseases. Meiotic processes occur in the context of chromatin; therefore, histone post-translational modifications are expected to play important roles. Here, we report the cytological distribution of the evolutionarily conserved DOT1L methyltransferase and the different H3K79 methylation states resulting from its activity (mono-, di- and tri-methylation; H3K79me1, me2 and me3, respectively) during meiotic prophase I in mouse spermatocytes. In the wild type, whereas low amounts of H3K79me1 are rather uniformly present throughout prophase I, levels of DOT1L, H3K79me2 and H3K79me3 exhibit a notable increase from pachynema onwards, but with differential subnuclear distribution patterns. The heterochromatic centromeric regions and the sex body are enriched for H3K79me3. In contrast, H3K79me2 is present all over the chromatin, but is largely excluded from the sex body despite the accumulation of DOT1L. In meiosis-defective mouse mutants, the increase of DOT1L and H3K79me is blocked at the same stage where meiosis is arrested. H3K79me patterns, combined with the cytological analysis of the H3.3, γH2AX, macroH2A and H2A.Z histone variants, are consistent with a differential role for these epigenetic marks in male mouse meiotic prophase I. We propose that H3K79me2 is related to transcriptional reactivation on autosomes during pachynema, whereas H3K79me3 may contribute to the maintenance of repressive chromatin at centromeric regions and the sex body.

| S-EPMC3969405 | biostudies-literature

High Mobility Group A2 protects cancer cells against telomere dysfunction.

Project description:The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.

| S-EPMC4914320 | biostudies-literature

High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis.

Project description:The high-mobility group A2 gene (HMGA2) is one of the most frequently amplified genes in human cancers. However, functions of HMGA2 in tumorigenesis are not fully understood due to limited knowledge of its targets in tumor cells. Our study reveals a novel link between HMGA2 and the regulation of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, which offers critical insight into how HMGA2 contributes to tumorigenesis. The expression of HMGA2 modulates the expression of hTERT, resulting in cells with enhanced telomerase activities and increased telomere length. Treatment with suberoylanilide hydroxamide (SAHA), a histone deacetylase (HDAC) inhibitor, causes dose-dependent hTERT reporter activation, mimicking HMGA2 overexpression. By interacting with Sp1, HMGA2 interferes with the recruitment of HDAC2 to the hTERT proximal promoter, enhancing localized histone H3-K9 acetylation and thereby stimulating hTERT expression and telomerase activity. Moreover, HMGA2 knockdown by short hairpin HMGA2 in HepG2 cells leads to progressive telomere shortening and a concurrent decrease of steady-state hTERT mRNA levels, attenuating their ability to form colonies in soft agar. Importantly, HMGA2 partially replaces the function of hTERT during the tumorigenic transformation of normal human fibroblasts. These findings are potentially clinically relevant, because HMGA2 expression is reported to be upregulated in a number of human cancers as telomere maintenance is essential for tumorigenesis.

| S-EPMC3133373 | biostudies-literature

Overlapping Roles for PLK1 and Aurora A During Meiotic Centrosome Biogenesis in Mouse Spermatocytes

Project description:Establishment of bipolar spindles during meiotic divisions ensures faithful chromosome segregation to prevent gamete aneuploidy. We analyzed centriole duplication, as well as centrosome maturation and separation during meiosis I and II using mouse spermatocytes. The first round of centriole duplication occurs during early prophase I, then centrosomes mature and begin to separate by the end of prophase I to prime formation of bipolar metaphase I spindles. A second round of centriole duplication occurs at late anaphase I, and, subsequently, centrosome separation coordinates bipolar segregation of sister chromatids during meiosis II. Using a germ-cell specific conditional knockout strategy, we show that Polo-like kinase 1 and Aurora A kinase are required for centrosome maturation and separation prior to metaphase I, leading to the formation of bipolar metaphase I spindles. Furthermore, we show that PLK1 is required to block the second round of centriole duplication and maturation until anaphase I. Our findings emphasize the importance of maintaining strict spatiotemporal control of cell cycle kinases during meiosis to ensure proficient centrosome biogenesis and, thus, accurate chromosome segregation during spermatogenesis.

| S-SCDT-EMBOR-2020-51023V1 | biostudies-other

The molecular chaperone Hsp90? is required for meiotic progression of spermatocytes beyond pachytene in the mouse.

Project description:The molecular chaperone Hsp90 has been found to be essential for viability in all tested eukaryotes, from the budding yeast to Drosophila. In mammals, two genes encode the two highly similar and functionally largely redundant isoforms Hsp90? and Hsp90?. Although they are co-expressed in most if not all cells, their relative levels vary between tissues and during development. Since mouse embryos lacking Hsp90? die at implantation, and despite the fact that Hsp90 inhibitors being tested as anti-cancer agents are relatively well tolerated, the organismic functions of Hsp90 in mammals remain largely unknown. We have generated mouse lines carrying gene trap insertions in the Hsp90? gene to investigate the global functions of this isoform. Surprisingly, mice without Hsp90? are apparently normal, with one major exception. Mutant male mice, whose Hsp90? levels are unchanged, are sterile because of a complete failure to produce sperm. While the development of the male reproductive system appears to be normal, spermatogenesis arrests specifically at the pachytene stage of meiosis I. Over time, the number of spermatocytes and the levels of the meiotic regulators and Hsp90 interactors Hsp70-2, NASP and Cdc2 are reduced. We speculate that Hsp90? may be required to maintain and to activate these regulators and/or to disassemble the synaptonemal complex that holds homologous chromosomes together. The link between fertility and Hsp90 is further supported by our finding that an Hsp90 inhibitor that can cross the blood-testis barrier can partially phenocopy the genetic defects.

| S-EPMC3013136 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data