PCH-2 collaborates with CMT-1 to proofread meiotic homolog interactions

Giacopazzi, Stefani; Vong, Daniel; Devigne, Alice; Bhalla, Needhi

doi:10.1371/journal.pgen.1008904

Cited by 19 publications

(31 citation statements)

References 78 publications

(116 reference statements)

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“…It has been proposed that Pch2 catalyzes the transition from the "closed" to the "unbuckled" conformation releasing the safety belt lock from the HORMA domain core [44]. Contrary to what is described in plants, worms and mammals, this action of Pch2 does not involve the p31 COMET co-factor, which is absent in budding yeast [38,[47][48][49].…”

Section: Introductionmentioning

confidence: 91%

“…We envision that the emerging cytoplasmic function of Pch2 in the meiotic recombination checkpoint may be evolutionarily conserved. In C. elegans, PCH-2 localizes to pachytene chromosomes suggesting a direct local role for PCH-2 in regulating recombination, likely by unlocking HORMAD proteins in collaboration with the CMT-1 cofactor [45,49]. However, worm PCH-2 is also required for the meiotic checkpoint induced in the synapsis-defective syp-1 mutant [72].…”

Section: Nucleocytoplasmic Communication Underlies Meiotic Checkpoint Functionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 91%

Section: Nucleocytoplasmic Communication Underlies Meiotic Checkpoint Functionmentioning

confidence: 99%

Pch2 orchestrates the meiotic recombination checkpoint from the cytoplasm

et al. 2021

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“…p31comet is an HORMA-domain-containing protein (Yang et al 2007 ) and is key in enabling the interaction of Pch2/TRIP13 with other HORMA proteins, such as Mad2 and Rev7 (Clairmont et al 2020 ; Eytan et al 2014 ; Ma and Poon 2016 ; Miniowitz-Shemtov et al 2015 ; Sarangi et al 2020 ; Ye et al 2015 , 2017 ). Recent work demonstrated that in plants ( A. thaliana and Oryza sativa ), as well as C. elegans, p31comet is also involved in Pch2/TRIP13 mediated effects on meiotic HORMADs (Balboni et al 2020 ; Giacopazzi et al 2020 ; Ji et al 2016 ). In A. thaliana , p31comet is needed for the recruitment of Pch2/TRIP13 to chromosomes (Balboni et al 2020 ), but in C. elegans , this does not seem to be the case (Balboni et al 2020 ; Giacopazzi et al 2020 ).…”

Section: Meiosismentioning

confidence: 99%

“…Recent work demonstrated that in plants ( A. thaliana and Oryza sativa ), as well as C. elegans, p31comet is also involved in Pch2/TRIP13 mediated effects on meiotic HORMADs (Balboni et al 2020 ; Giacopazzi et al 2020 ; Ji et al 2016 ). In A. thaliana , p31comet is needed for the recruitment of Pch2/TRIP13 to chromosomes (Balboni et al 2020 ), but in C. elegans , this does not seem to be the case (Balboni et al 2020 ; Giacopazzi et al 2020 ). No clear p31comet homolog has been described in budding yeast.…”

Section: Meiosismentioning

confidence: 99%

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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“…PCH-2 is a highly-conserved AAA+ ATPase that is required for the synapsis checkpoint [2] and coordinates the events of pairing, synapsis and recombination to ensure their fidelity [13,14]. Since ΔN-mdf-1 mad-1 deletion mutants abrogated the synapsis checkpoint but did not perturb synapsis, we tested whether PCH-2 localization was affected in this background.…”

Section: Mdf-1 Mad-1 'S Localization To Nuclear Envelope Is Required For the Synapsis Checkpoint But Not To Regulate Synapsismentioning

confidence: 99%

Mad1’s ability to interact with Mad2 is essential to regulate and monitor meiotic synapsis in C. elegans

Devigne

Bhalla

2021

PLoS Genet

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Meiotic homolog synapsis is essential to ensure accurate segregation of chromosomes during meiosis. In C. elegans, proper regulation of synapsis and a checkpoint that monitors synapsis relies on the spindle checkpoint components, Mad1 and Mad2, and Pairing Centers (PCs), cis-acting loci that interact with the nuclear envelope to mobilize chromosomes within the nucleus. Here, we test what specific functions of Mad1 and Mad2 are required to regulate and monitor synapsis. We find that a mutation that prevents Mad1’s localization to the nuclear periphery abolishes the synapsis checkpoint but has no effect on Mad2’s localization to the nuclear periphery or synapsis. By contrast, a mutation that prevents Mad1’s interaction with Mad2 abolishes the synapsis checkpoint, delays synapsis and fails to localize Mad2 to the nuclear periphery. These data indicate that Mad1’s primary role in regulating synapsis is through control of Mad2 and that Mad2 can bind other factors at the nuclear periphery. We also tested whether Mad2’s ability to adopt a specific conformation associated with its activity during spindle checkpoint function is required for its role in meiosis. A mutation that prevents Mad2 from adopting its active conformer fails to localize to the nuclear periphery, abolishes the synapsis checkpoint and exhibits substantial defects in meiotic synapsis. Thus, Mad2, and its regulation by Mad1, is an important regulator of meiotic synapsis in C. elegans.

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PCH-2 collaborates with CMT-1 to proofread meiotic homolog interactions

Cited by 19 publications

References 78 publications

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

Mad1’s ability to interact with Mad2 is essential to regulate and monitor meiotic synapsis in C. elegans

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