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The role of bivalent ions in the regulation of D-loop extension mediated by DMC1 during meiotic recombination.

ABSTRACT: During meiosis, programmed DNA double-strand breaks (DSBs) are repaired by homologous recombination. DMC1, a conserved recombinase, plays a central role in this process. DMC1 promotes DNA strand exchange between homologous chromosomes, thus creating the physical linkage between them. Its function is regulated not only by several accessory proteins but also by bivalent ions. Here, we show that whereas calcium ions in the presence of ATP cause a conformational change within DMC1, stimulating its DNA binding and D-loop formation, they inhibit the extension of the invading strand within the D-loop. Based on structural studies, we have generated mutants of two highly conserved amino acids - E162 and D317 - in human DMC1, which are deficient in calcium regulation. In vivo studies of their yeast homologues further showed that they exhibit severe defects in meiosis, thus emphasizing the importance of calcium ions in the regulation of DMC1 function and meiotic recombination.

SUBMITTER: Altmannova V

PROVIDER: S-EPMC9641244 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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The role of bivalent ions in the regulation of D-loop extension mediated by DMC1 during meiotic recombination.

Altmannova Veronika V Spirek Mario M Orlic Lucija L Jēkabsons Atis A Clarence Tereza T Henggeler Adrian A Mlcouskova Jarmila J Chaleil Raphaël A G RAG Matos Joao J Krejci Lumir L

iScience 20221025 11

During meiosis, programmed DNA double-strand breaks (DSBs) are repaired by homologous recombination. DMC1, a conserved recombinase, plays a central role in this process. DMC1 promotes DNA strand exchange between homologous chromosomes, thus creating the physical linkage between them. Its function is regulated not only by several accessory proteins but also by bivalent ions. Here, we show that whereas calcium ions in the presence of ATP cause a conformational change within DMC1, stimulating its D ...[more]

PMID: 36388968

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Project description:Rationale: Meiotic homologous recombination is a critical event in gametogenesis, which is tightly regulated to ensure the generation of crossovers on homologous chromosomes. This process is crucial for ensuring the accurate segregation of genetic material and maintaining genetic diversity within species, ultimately contributing to reproductive success. Nevertheless, comprehensive mechanisms of post-translational modification (PTM) regulating homologous recombination during meiosis require further investigation. The aim of this study is to investigate the regulatory mechanisms and physiological functions of NAE1-mediated neddylation during meiosis of mammalian spermatogenesis and its consequential role in infertility. Methods: The dynamic localization of NAE1 at various sub-stages during spermatogenesis was determined using immunofluorescence staining and seminiferous tubule staging. We explore the role of NAE1-mediated neddylation by utilizing germ cell-specific Nae1-knockout mice. The impact on homologous synapsis and recombination during the meiosis prophase I were verified through chromosome spread fluorescence staining. We used 10 × Genomics single cell transcriptomics and ubiquitinomics to analysis the causes of spermatogenesis arrest and spermatogenic apoptosis. Results: NAE1 exhibited high nuclear expression within spermatocytes from the pachytene stage onwards. Nae1-SKO male mice showed a late-pachytene arrest in spermatocytes, resulting in infertility. In NAE1-deficient spermatocytes, there is an increase in apoptosis. Nae1 deletion led to double-strand break (DSB) repair failure with normal autosomes synapsis. From a mechanistic perspective, we verified excessive recombination intermediate stabilization and failed crossover formation, which ultimately resulted in impaired meiotic recombination. Further analysis showed that ubiquitination regulation coordinated with NAE1-mediated neddylation was implicated in meiotic recombination. Conclusion: NAE1-mediated neddylation regulates ubiquitination during meiosis and is involved in the stabilization of recombination proteins related to crossover differentiation. We provide cytological evidence for the neddylation-ubiquitination system (NUS) in mammalian meiotic recombination during spermatogenesis.

Dataset Information

The role of bivalent ions in the regulation of D-loop extension mediated by DMC1 during meiotic recombination.

Publications

The role of bivalent ions in the regulation of D-loop extension mediated by DMC1 during meiotic recombination.

Similar Datasets

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