Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases orchestrate the correct assembly and activity of the repair machinery. Although much less is known, the reversal of phosphorylation events in meiosis must also be key to coordinate the timing and functionality of repair enzymes. Cdc14 is a crucial phosphatase required for the dephosphorylation of multiple CDK1 targets in many eukaryotes. Mutations that inactivate this phosphatase lead to meiotic failure, but until now it was unknown if Cdc14 plays a direct role in meiotic recombination. Here, we show that the elimination of Cdc14 leads to severe defects in the processing and resolution of recombination intermediates, causing a drastic depletion in crossovers when other repair pathways are compromised. We also show that Cdc14 is required for the correct activity and localization of the Holliday Junction resolvase Yen1/GEN1. We reveal that Cdc14 regulates Yen1 activity from meiosis I onwards, and this function is essential for crossover resolution in the absence of other repair pathways. We also demonstrate that Cdc14 and Yen1 are required to safeguard sister chromatid segregation during the second meiotic division, a late action that is independent of the earlier role in crossover formation. Thus, this work uncovers previously undescribed functions of the evolutionary conserved Cdc14 phosphatase in the regulation of meiotic recombination.
- Klíčová slova
- CDK1, Cdc14, Cdc20, Cdc5, Holliday junction, Mus81, Ndt80, Sgs1, Yen1, aneuploidy, meiotic recombination,
- MeSH
- crossing over (genetika) genetika MeSH
- fosforylace genetika MeSH
- gametogeneze genetika MeSH
- homologní rekombinace genetika MeSH
- křížová struktura DNA genetika MeSH
- meióza genetika MeSH
- mutace genetika MeSH
- oprava DNA genetika MeSH
- proteinkinasa CDC2 genetika MeSH
- proteiny buněčného cyklu genetika MeSH
- resolvasy Hollidayova spojení genetika MeSH
- Saccharomyces cerevisiae - proteiny genetika MeSH
- Saccharomyces cerevisiae genetika MeSH
- segregace chromozomů genetika MeSH
- tyrosinfosfatasy genetika MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CDC14 protein, S cerevisiae MeSH Prohlížeč
- křížová struktura DNA MeSH
- proteinkinasa CDC2 MeSH
- proteiny buněčného cyklu MeSH
- resolvasy Hollidayova spojení MeSH
- Saccharomyces cerevisiae - proteiny MeSH
- tyrosinfosfatasy MeSH
- Yen1 protein, S cerevisiae MeSH Prohlížeč
Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
- Klíčová slova
- FDG Abs, Fab dimerization, HIV-1 Env glycans, IgM-memory B cells, SARS-CoV-2 spike glycans, glycan-dependent Ab binding, marginal zone B cells, natural Abs,
- MeSH
- B-lymfocyty imunologie MeSH
- COVID-19 imunologie MeSH
- dimerizace MeSH
- epitopy imunologie MeSH
- genové produkty env - virus lidské imunodeficience chemie genetika imunologie MeSH
- glykoprotein S, koronavirus imunologie MeSH
- glykosylace MeSH
- HIV infekce imunologie MeSH
- HIV protilátky imunologie MeSH
- HIV-1 imunologie MeSH
- imunoglobuliny - Fab fragmenty chemie imunologie MeSH
- lidé MeSH
- Macaca mulatta MeSH
- neutralizující protilátky imunologie MeSH
- polysacharidy chemie imunologie MeSH
- receptory antigenů B-buněk chemie MeSH
- SARS-CoV-2 imunologie MeSH
- široce neutralizující protilátky imunologie MeSH
- vakcíny imunologie MeSH
- virus opičí imunodeficience genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- epitopy MeSH
- genové produkty env - virus lidské imunodeficience MeSH
- glykoprotein S, koronavirus MeSH
- HIV protilátky MeSH
- imunoglobuliny - Fab fragmenty MeSH
- neutralizující protilátky MeSH
- polysacharidy MeSH
- receptory antigenů B-buněk MeSH
- široce neutralizující protilátky MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
- vakcíny MeSH
