DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans

Lascarez-Lagunas, Laura I; Herruzo, Esther; Grishok, Alla; San-Segundo, Pedro A.; Colaiácovo, Mónica P.

doi:10.1371/journal.pgen.1009171

Cited by 14 publications

(11 citation statements)

References 82 publications

(156 reference statements)

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“…However, worm PCH-2 is also required for the meiotic checkpoint induced in the synapsis-defective syp-1 mutant [72]. In this scenario, PCH-2 does not localize to chromosomes, opening the possibility that the diffuse extranuclear PCH-2 signal observed in syp-1 [73,74], analogous to the cytoplasmic distribution of budding yeast Pch2 characterized here, may be relevant for the checkpoint in worms.…”

Section: Nucleocytoplasmic Communication Underlies Meiotic Checkpoint Functionmentioning

confidence: 69%

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

et al. 2021

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During meiosis, defects in critical events trigger checkpoint activation and restrict cell cycle progression. The budding yeast Pch2 AAA+ ATPase orchestrates the checkpoint response launched by synapsis deficiency; deletion of PCH2 or mutation of the ATPase catalytic sites suppress the meiotic block of the zip1Δ mutant lacking the central region of the synaptonemal complex. Pch2 action enables adequate levels of phosphorylation of the Hop1 axial component at threonine 318, which in turn promotes activation of the Mek1 effector kinase and the ensuing checkpoint response. In zip1Δ chromosomes, Pch2 is exclusively associated to the rDNA region, but this nucleolar fraction is not required for checkpoint activation, implying that another yet uncharacterized Pch2 population must be responsible for this function. Here, we have artificially redirected Pch2 to different subcellular compartments by adding ectopic Nuclear Export (NES) or Nuclear Localization (NLS) sequences, or by trapping Pch2 in an immobile extranuclear domain, and we have evaluated the effect on Hop1 chromosomal distribution and checkpoint activity. We have also deciphered the spatial and functional impact of Pch2 regulators including Orc1, Dot1 and Nup2. We conclude that the cytoplasmic pool of Pch2 is sufficient to support the meiotic recombination checkpoint involving the subsequent Hop1-Mek1 activation on chromosomes, whereas the nuclear accumulation of Pch2 has pathological consequences. We propose that cytoplasmic Pch2 provokes a conformational change in Hop1 that poises it for its chromosomal incorporation and phosphorylation. Our discoveries shed light into the intricate regulatory network controlling the accurate balance of Pch2 distribution among different cellular compartments, which is essential for proper meiotic outcomes.

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Section: Nucleocytoplasmic Communication Underlies Meiotic Checkpoint Functionmentioning

confidence: 69%

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

et al. 2021

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“…However, worm PCH-2 is also required for the meiotic checkpoint induced in the synapsis-defective syp-1 mutant (Bhalla and Dernburg, 2005). In this scenario, PCH-2 does not localize to chromosomes, opening the possibility that the diffuse extranuclear PCH-2 signal observed in syp-1 (Deshong et al, 2014;Lascarez-Lagunas et al, 2020b), analogous to the cytoplasmic distribution of budding yeast Pch2 characterized here, may be relevant for the checkpoint in worms.…”

Section: Nucleocytoplasmic Communication Underlies Meiotic Checkpoint Functionmentioning

confidence: 69%

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

Herruzo

Lago-Maciel

Baztán

et al. 2021

Preprint

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During meiosis, defects in critical events trigger checkpoint activation and restrict cell cycle progression. The budding yeast Pch2 AAA+ ATPase orchestrates the checkpoint response launched by synapsis deficiency; deletion of PCH2 or mutation of the ATPase catalytic sites suppress the meiotic block of the zip1Δ mutant lacking the central region of the synaptonemal complex. Pch2 action enables adequate levels of phosphorylation of the Hop1 axial component at threonine 318, which in turn promotes activation of the Mek1 effector kinase and the ensuing checkpoint response. In zip1Δ chromosomes, Pch2 is exclusively associated to the rDNA region, but this nucleolar fraction is not required for checkpoint activation, implying that another yet uncharacterized Pch2 population must be responsible for this function. Here, we have artificially redirected Pch2 to different subcellular compartments by adding ectopic NES or NLS sequences or by trapping Pch2 in an immobile extranuclear domain, and we have evaluated the effect on Hop1 chromosomal distribution and checkpoint activity. We have also deciphered the spatial and functional impact of Pch2 regulators including Orc1, Dot1 and Nup2. We conclude that the cytoplasmic pool of Pch2 is sufficient to support the meiotic recombination checkpoint involving the subsequent Hop1-Mek1 activation on chromosomes, whereas the nuclear accumulation of Pch2 has pathological consequences. We propose that cytoplasmic Pch2 provokes a conformational change in Hop1 that poises it for its chromosomal incorporation and phosphorylation. Our discoveries shed light into the intricate regulatory network controlling the accurate balance of Pch2 distribution among different cellular compartments, which is essential for proper meiotic outcomes.

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“…However, in Drosophila melanogaster , Sir2 is linked to Pch2 function in meiosis (Joyce and McKim 2010 ), and it will be interesting to carefully examine the possible association of Pch2 with nucleolar regions in species other than budding yeast. In relation to this, a recent study in C. elegans revealed a role for Dot1 in checkpoint control (Lascarez-Lagunas et al 2020 ), as in budding yeast (San-Segundo and Roeder 1999 , 2000 ). However, there is currently no evidence that this function is directly connected to Pch2 localization to chromosomes (or the rDNA/nucleolus) (Lascarez-Lagunas et al 2020 ).…”

Section: Meiosismentioning

confidence: 94%

“…In relation to this, a recent study in C. elegans revealed a role for Dot1 in checkpoint control (Lascarez-Lagunas et al 2020 ), as in budding yeast (San-Segundo and Roeder 1999 , 2000 ). However, there is currently no evidence that this function is directly connected to Pch2 localization to chromosomes (or the rDNA/nucleolus) (Lascarez-Lagunas et al 2020 ).…”

Section: Meiosismentioning

confidence: 94%

Getting there: understanding the chromosomal recruitment of the AAA+ ATPase Pch2/TRIP13 during meiosis

Silva

Vader

2021

Curr Genet

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The generally conserved AAA+ ATPase Pch2/TRIP13 is involved in diverse aspects of meiosis, such as prophase checkpoint function, DNA break regulation, and meiotic recombination. The controlled recruitment of Pch2 to meiotic chromosomes allows it to use its ATPase activity to influence HORMA protein-dependent signaling. Because of the connection between Pch2 chromosomal recruitment and its functional roles in meiosis, it is important to reveal the molecular details that govern Pch2 localization. Here, we review the current understanding of the different factors that control the recruitment of Pch2 to meiotic chromosomes, with a focus on research performed in budding yeast. During meiosis in this organism, Pch2 is enriched within the nucleolus, where it likely associates with the specialized chromatin of the ribosomal (r)DNA. Pch2 is also found on non-rDNA euchromatin, where its recruitment is contingent on Zip1, a component of the synaptonemal complex (SC) that assembles between homologous chromosomes. We discuss recent findings connecting the recruitment of Pch2 with its association with the Origin Recognition Complex (ORC) and reliance on RNA Polymerase II-dependent transcription. In total, we provide a comprehensive overview of the pathways that control the chromosomal association of an important meiotic regulator.

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DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans

Cited by 14 publications

References 82 publications

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

Getting there: understanding the chromosomal recruitment of the AAA+ ATPase Pch2/TRIP13 during meiosis

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