“…Thus, SKP1 could inhibit accumulation of HORMAD1 on both synapsed and unsynapsed SCs in Skp1 mutant spermatocytes through the same mechanism. To identify the F-box proteins that recognize HORMAD1, we chose several potential candidates: FBXW8, FBXW17, FBXO28 and FBXO47, because peptides of FBXW8, FBXW17, and FBXO28 were present in the same mass spectrometry dataset that identified SKP1 and HORMAD1 ( 18 ) and FBXO47-deficient mice showed meiotic arrest ( 54 , 55 ). F-box proteins physically interact with their substrate proteins ( 56 ).…”
Section: Resultsmentioning
confidence: 99%
“…Co-transfections in HEK293T cells show that SCF-FBXO47 targets HORMAD1 for polyubiquitination. However, FBXO47 is unlikely to be the sole F-box protein required for chromosomal synapsis in mice, since Skp1 cKO spermatocytes completely lack synapsis but the FBXO47-deficient spermatocytes still display substantial synapsis, indicating that additional F-box proteins are involved ( 54 , 55 ). C. elegans Prom-1 is a homologue of FBXO47.…”
Homeostasis of meiotic DNA double strand breaks (DSB) is critical for germline genome integrity and homologous recombination. Here we demonstrate an essential role for SKP1, a constitutive subunit of the SCF (SKP1-Cullin-F-box) ubiquitin E3 ligase, in early meiotic processes. SKP1 restrains accumulation of HORMAD1 and the pre-DSB complex (IHO1-REC114-MEI4) on the chromosome axis in meiotic germ cells. Loss of SKP1 prior to meiosis leads to aberrant localization of DSB repair proteins and a failure in synapsis initiation in meiosis of both males and females. Furthermore, SKP1 is crucial for sister chromatid cohesion during the pre-meiotic S-phase. Mechanistically, FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells. Our results support a model wherein the SCF ubiquitin E3 ligase prevents hyperactive DSB formation through proteasome-mediated degradation of HORMAD1 and subsequent modulation of the pre-DSB complex during meiosis.
“…Thus, SKP1 could inhibit accumulation of HORMAD1 on both synapsed and unsynapsed SCs in Skp1 mutant spermatocytes through the same mechanism. To identify the F-box proteins that recognize HORMAD1, we chose several potential candidates: FBXW8, FBXW17, FBXO28 and FBXO47, because peptides of FBXW8, FBXW17, and FBXO28 were present in the same mass spectrometry dataset that identified SKP1 and HORMAD1 ( 18 ) and FBXO47-deficient mice showed meiotic arrest ( 54 , 55 ). F-box proteins physically interact with their substrate proteins ( 56 ).…”
Section: Resultsmentioning
confidence: 99%
“…Co-transfections in HEK293T cells show that SCF-FBXO47 targets HORMAD1 for polyubiquitination. However, FBXO47 is unlikely to be the sole F-box protein required for chromosomal synapsis in mice, since Skp1 cKO spermatocytes completely lack synapsis but the FBXO47-deficient spermatocytes still display substantial synapsis, indicating that additional F-box proteins are involved ( 54 , 55 ). C. elegans Prom-1 is a homologue of FBXO47.…”
Homeostasis of meiotic DNA double strand breaks (DSB) is critical for germline genome integrity and homologous recombination. Here we demonstrate an essential role for SKP1, a constitutive subunit of the SCF (SKP1-Cullin-F-box) ubiquitin E3 ligase, in early meiotic processes. SKP1 restrains accumulation of HORMAD1 and the pre-DSB complex (IHO1-REC114-MEI4) on the chromosome axis in meiotic germ cells. Loss of SKP1 prior to meiosis leads to aberrant localization of DSB repair proteins and a failure in synapsis initiation in meiosis of both males and females. Furthermore, SKP1 is crucial for sister chromatid cohesion during the pre-meiotic S-phase. Mechanistically, FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells. Our results support a model wherein the SCF ubiquitin E3 ligase prevents hyperactive DSB formation through proteasome-mediated degradation of HORMAD1 and subsequent modulation of the pre-DSB complex during meiosis.
“…We previously generated Stra8 - 3xFLAG-HA-p2A-GFP knock-in ( Stra8 - 3FH-GFP KI) mice, which had 3xFLAG-HA tagged STRA8 protein expressed in the testis ( Ishiguro et al., 2020 ) From the nuclear fraction of Stra8 - 3FH-GFP KI testes, we identified MEIOSIN as a STRA8 interacting protein that directs the switching from mitosis to meiosis ( Ishiguro et al., 2020 ). The same strategy is essentially applicable to any proteins that are expressed in the testis ( Tanno et al., 2022 ). Figure 1 Expression of 3xFLAG-HA fusion protein in knockin mouse testis (A) Schematic illustrations of the Fbxo47-3xFLAG-HA knock-in alleles, which were used in our experiments ( Tanno et al., 2022 ).…”
Section: Before You Beginmentioning
confidence: 99%
“…For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2020) and Tanno et al. (2022) .…”
“…Caenorhabditis elegans FBXO47 (also known as PROM-1) mediates the mitosis-meiosis transition via ubiquitination and degradation of cyclin E1 (CYE-1), and SCFPROM-1 also promotes homologous chromosome pairing as a positive regulator of CHK-2 serine/threonine kinase ( Mohammad et al, 2018 ). In addition, a recent study revealed that mouse Fbxo47 prevents precocious disassembly of the synaptonemal complex independently of SCF E3 ligase ( Tanno et al, 2022 ). Thus, Fbxo47 may have conserved roles in gametogenesis via ubiquitination-dependent and ubiquitination-independent pathways.…”
Gametogenesis, the production of eggs and sperm, is a fundamental process in sexually reproducing animals. Following gametogenesis commitment and sexual fate decision, germ cells undergo several developmental processes to halve their genomic size and acquire sex-specific characteristics of gametes, including cellular size, motility, and cell polarity. However, it remains unclear how different gametogenesis processes are initially integrated. With the advantages of the teleost fish medaka (Oryzias latipes), in which germline stem cells continuously produce eggs and sperm in mature gonads and a sexual switch gene in germ cells is identified, we found that distinct pathways initiate gametogenesis cooperatively after commitment to gametogenesis. This evokes the concept of functional modules, in which functionally interlocked genes are grouped to yield distinct gamete characteristics. The various combinations of modules may allow us to explain the evolution of diverse reproductive systems, such as parthenogenesis and hermaphroditism.
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