TOPBP1 Shapes XY Silencing Dynamics during Meiosis to Ensure Male Fertility
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232588 | GEO | 2024/02/09
REPOSITORIES: GEO
Similar Datasets
Project description:In mammals and several other taxa, the ability of males to cope with the limited synapsis of the X and Y chromosomes during prophase I of meiosis relies on the process of meiotic sex chromosome inactivation (MSCI). Components of the somatic DNA damage response machinery, including ATR, TOPBP1, MDC1 and BRCA1 play key roles in MSCI, although how they establish XY silencing remains incompletely understood. In particular, it remains unclear how DDR factors coordinate XY silencing with DNA repair, chromosome synapsis and the formation of the sex body, a distinct phase-separated sub-nuclear structure formed during prophase I to house the unsynapsed XY bivalent. Here we report a mutant mouse (Topbp1B5/B5), harboring mutations in the BRCT5 domain of Topbp1, that shows impaired XY silencing but grossly normal sex body formation. While Topbp1B5/B5 mice are viable, without detectable somatic defects, males are completely infertile. Distinct from mice lacking ATR or TOPBP1 specifically during meiosis, Topbp1B5/B5 males exhibit normal chromosome synapsis and canonical markers of DNA repair in early prophase I. ATR signaling is mostly intact in Topbp1B5/B5 spermatocytes, although specific ATR-dependent events are disrupted, including localization of the RNA:DNA helicase Senataxin to chromatin loops of the XY. Strikingly, while Topbp1B5/B5 spermatocytes are able to initiate MSCI the completion of gene silencing is defective, with a subset of X chromosome genes displaying distinct patterns of transcriptional deregulation. These findings suggest a non-canonical role for the ATR-TOPBP1 signaling axis in XY silencing dynamics at advanced stages in pachynema. This is the first DDR mutant that separates XY silencing from sex body formation, as well as TOPBP1’s role in spermatogenesis from its roles in organismal viability.
2024-02-09 | PXD042199 | Pride
Project description:TOPBP1 Shapes XY Silencing Dynamics during Meiosis to Ensure Male Fertility
| PRJNA972765 | ENA
Project description:We report the TopBP1 associated with RNA via using sequencing of RNA isolated by PAR-CLIP.
2022-09-23 | GSE213073 | GEO
Project description:We investigate the implications of DNA double strand breaks in the human genome, regarding the progression and treatment of various cancer types. During mitosis, the canonical DNA repair mechanisms are suspended while broken chromosomes get temporarily stabilized through so-called adapter proteins. We already knew that TOPBP1 is involved in that process and recently, we identified another Protein which recruits TOPBP1 to sites of damage. After mapping the interaction site on TOPBP1 we attempted to pull down CIP2A using a fragment of the binding domain, followed by chromatography-tandem-mass spectrometry analysis, the results of which we share in this upload.
2022-07-19 | PXD034100 | Pride
Project description:DNA topoisomerase II-binding protein 1 (TopBP1) plays a vital role in V(D)J recombination during B and T cell development. However, its role in the development of conventional dendritic cells (cDCs) remains unexplored. Mice with DC-specific depletion of TopBP1 (TopBP1cKO) showed accelerated tumor progression due to impaired anti-tumor immunity, characterized by cDC deficiency and pre-DC accumulation. Notably, Flt3 ligand (Flt3L)-mediated tumor immunotherapy was ineffective in TopBP1cKO tumor-bearing mice. Our study demonstrates that TopBP1 is required not only for the steady-state differentiation of total cDCs, including both cDC1 and cDC2, but also for the terminal differentiation of XCR1⁻CD24⁺ emergency progenitors (EPs; CD11c⁺cKit⁺) into XCR1⁺CD24⁺ cDC1s in response to Flt3L. Furthermore, we revealed that TopBP1 directly interacts with PU.1 and IRF8, key transcription factors (TFs) required for cDC development, triggering the expression of their downstream target genes. These findings identify TopBP1 as a crucial factor for cDC development and Flt3L-driven EP differentiation into cDC1s, revealing that the function of key TFs for cDC development is mediated via interaction with TopBP1. Our work underscores the importance of TopBP1 in promoting cDC development and the therapeutic efficacy of Flt3L-mediated tumor immunotherapy.
2026-02-26 | GSE300836 | GEO
Project description:DNA topoisomerase II-binding protein 1 (TopBP1) plays a vital role in V(D)J recombination during B and T cell development. However, its role in the development of conventional dendritic cells (cDCs) remains unexplored. Mice with DC-specific depletion of TopBP1 (TopBP1cKO) showed accelerated tumor progression due to impaired anti-tumor immunity, characterized by cDC deficiency and pre-DC accumulation. Notably, Flt3 ligand (Flt3L)-mediated tumor immunotherapy was ineffective in TopBP1cKO tumor-bearing mice. Our study demonstrates that TopBP1 is required not only for the steady-state differentiation of total cDCs, including both cDC1 and cDC2, but also for the terminal differentiation of XCR1⁻CD24⁺ emergency progenitors (EPs; CD11c⁺cKit⁺) into XCR1⁺CD24⁺ cDC1s in response to Flt3L. Furthermore, we revealed that TopBP1 directly interacts with PU.1 and IRF8, key transcription factors (TFs) required for cDC development, triggering the expression of their downstream target genes. These findings identify TopBP1 as a crucial factor for cDC development and Flt3L-driven EP differentiation into cDC1s, revealing that the function of key TFs for cDC development is mediated via interaction with TopBP1. Our work underscores the importance of TopBP1 in promoting cDC development and the therapeutic efficacy of Flt3L-mediated tumor immunotherapy.
2025-12-16 | GSE301438 | GEO
Project description:TopBP1 is more than a DNA damage factor. The knockdown indicates it could have transcriptional regulatory function and we validated this by examining E2F1/p73 pathway.
2018-11-01 | GSE122018 | GEO
Project description:Mass spectrometry analysis of the differential binding proteins of TOPBP1/wt and TOPBP1/K250A.
2022-02-08 | PXD031501 |
Project description:BackgroundVertebrate meiotic recombination events are concentrated in regions (hotspots) that display open chromatin marks, such as trimethylation of lysines 4 and 36 of histone 3 (H3K4me3 and H3K36me3). Mouse and human PRDM9 proteins catalyze H3K4me3 and H3K36me3 and determine hotspot positions, whereas other vertebrates lacking PRDM9 recombine in regions with chromatin already opened for another function, such as gene promoters. While these other vertebrate species lacking PRDM9 remain fertile, inactivation of the mouse Prdm9 gene, which shifts the hotspots to the functional regions (including promoters), typically causes gross fertility reduction; and the reasons for these species differences are not clear.ResultsWe introduced Prdm9 deletions into the Rattus norvegicus genome and generated the first rat genome-wide maps of recombination-initiating double-strand break hotspots. Rat strains carrying the same wild-type Prdm9 allele shared 88% hotspots but strains with different Prdm9 alleles only 3%. After Prdm9 deletion, rat hotspots relocated to functional regions, about 40% to positions corresponding to Prdm9-independent mouse hotspots, including promoters. Despite the hotspot relocation and decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced healthy offspring. The percentage of normal pachytene spermatocytes in SHR-Prdm9 mutants was almost double than in the PWD male mouse oligospermic sterile mutants. We previously found a correlation between the crossover rate and sperm presence in mouse Prdm9 mutants. The crossover rate of SHR is more similar to sperm-carrying mutant mice, but it did not fully explain the fertility of the SHR mutants. Besides mild meiotic arrests at rat tubular stages IV (mid-pachytene) and XIV (metaphase), we also detected postmeiotic apoptosis of round spermatids. We found delayed meiosis and age-dependent fertility in both sexes of the SHR mutants.ConclusionsWe hypothesize that the relative increased fertility of rat versus mouse Prdm9 mutants could be ascribed to extended duration of meiotic prophase I. While rat PRDM9 shapes meiotic recombination landscapes, it is unnecessary for recombination. We suggest that PRDM9 has additional roles in spermatogenesis and speciation-spermatid development and reproductive age-that may help to explain male-specific hybrid sterility.
| S-EPMC8082845 | biostudies-literature
Project description:Abdominal aortic aneurysms (AAAs) are a prevalent and deadly human pathology with strong sexual dimorphism. Research demonstrates that sex hormones influence, but do not fully explain, male versus female AAA pathology. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, for the first time, we defined the effect of female (XX) versus male (XY) chromosome complement on AAA formation and rupture in phenotypically female mice using an established murine model. Abdominal aortas from female mice bearing the XY chromosome selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of gene differences in XY females fell within inflammatory pathways. When XY females were infused with AngII, AAA incidences doubled and aneurysms ruptured. AAAs from XY females exhibited significant inflammation. Moreover, infusion of AngII to XY females augmented aortic activity of matrix metalloproteinases. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX females. These results demonstrate that an XY sex chromosome complement profoundly influences aortic gene expression profiles and promotes AAA severity.
2016-11-07 | GSE81580 | GEO