The Pch2 AAA+ ATPase promotes phosphorylation of the Hop1 meiotic checkpoint adaptor in response to synaptonemal complex defects

Herruzo, Esther; Ontoso, David; González-Arranz, Sara; Cavero, Santiago; Lechuga, Ana; San-Segundo, Pedro A.

doi:10.1093/nar/gkw506

Cited by 48 publications

(114 citation statements)

References 77 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…The nucleolar pool of Pch2 is unlikely to be involved in checkpoint function [41], and work in Drosophila suggests that Pch2 is associated with nuclear lamina [41, 42]. In line with previous observations [43], Pch2 was required for phosphorylation of Hop1 in checkpoint activating conditions: we observed that the abundance of Hop1 and presence of Pch2 affected the phosphorylated pool of Hop1 (for example, compare wild type, pch2 dmc1, HOP1/hop1 dmc1 and pch2 HOP1/hop1 dmc1 in Figure 2F). Combined with our findings (see also above; Figure 1) and earlier work [41], these observations suggest a dynamic exchange between non-chromosomal and chromosomal ( i.e.…”

Section: Resultssupporting

confidence: 72%

Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1

Raina

Vader

2020

Preprint

View full text Add to dashboard Cite

17 Checkpoints cascades coordinate cell cycle progression with essential chromosomal 18 processes. During meiotic G2/prophase, recombination and chromosome synapsis are 19 monitored by what are considered distinct checkpoints [1-3]. In budding yeast, the AAA+ 20 ATPase Pch2 is thought to specifically promote cell cycle delay in response to synapsis defects 21 [4-6]. However, unperturbed pch2D cells are delayed in meiotic G2/prophase [6], suggesting 22 paradoxical roles for Pch2 in cell cycle progression. Here, we provide insight into the checkpoint 23 roles of Pch2 and its connection to Hop1, a HORMA domain-containing client protein. 24 Contrary to current understanding, we find that the Pch2-Hop1 module is crucial for 25 checkpoint function in response to both recombination and synapsis defects, thus revealing a 26 shared meiotic checkpoint cascade. Meiotic checkpoint responses are transduced by DNA 27 break-dependent phosphorylation of Hop1 [7, 8]. Based on our data and on the effect of Pch2 28 on HORMA topology [9-11], we propose that Pch2 promotes checkpoint proficiency by 29 catalyzing the availability of signaling-competent Hop1. Conversely, we demonstrate that Pch2 30 can act as a checkpoint silencer, also in the face of persistent DNA repair defects. We establish 31 a framework in which Pch2 and Hop1 form a homeostatic module that governs general meiotic 32 checkpoint function. We show that this module can -depending on the cellular context -fuel 33 or extinguish meiotic checkpoint function, which explains the contradictory roles of Pch2 in cell 34 cycle control. Within the meiotic checkpoint, the Pch2-Hop1 module thus operates analogous 35 to the Pch2/TRIP13-Mad2 module in the spindle assembly checkpoint that monitors 36 chromosome segregation [12-16]. 37 38 repair 40 41 Results and discussion 42 43 Feedback regulation between Hop1, Zip1 and Pch2 influences SC assembly 44 In G2/prophase of the meiotic program, double strand break (DSB) formation 45 recombinational repair, synapsis of homologous chromosomes is integrated with cell cycle 46 progression [17]. In budding yeast, Zip1-mediated Synaptonemal Complex (SC) assembly promotes 47 cell cycle progression by regulating chromosome-based checkpoint activity [18-20]. The 48 chromosome axis, of which Hop1 is a key component, forms the structural foundation for recruitment 49 of the SC [21]. The functionality of meiotic checkpoints that monitor recombination and synapsis is 50 linked to successful recombination and SC establishment, and the function of Pch2 is associated with 51 both Hop1 and Zip1: Hop1 is a client of Pch2 [22][23][24][25], and chromosomal association of Pch2 is tightly 52 linked to Zip1/SC establishment [5, 20, 23,[26][27][28][29]. To understand the wiring between these numerous 53 crucial events during meiotic G2/prophase and the role of Pch2 herein, we initially investigated SC 54 formation and its relation to Pch2, Hop1 and Zip1. 55 SC components, like Zip1, can form extrachromosomal aggregates known as polycomplexes 56 (PCs) [4]. Cells ...

show abstract

Section: Resultssupporting

confidence: 72%

Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1

Raina

Vader

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…According with the prominent localization pattern of Pch2 on chromosome spreads ( Fig. 2a) (San-Segundo and Roeder 1999;Herruzo et al 2016) and with the fact that this conspicuous GFP-Pch2 structure did not overlap with Hop1-mCherry ( Fig. 4d; Fig.…”

Section: Analysis Of Pch2 Localization In Whole Meiotic Cellsmentioning

confidence: 65%

Characterization of Pch2 localization determinants reveals a nucleolar-independent role in the meiotic recombination checkpoint

Herruzo

Santos

Freire

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The meiotic recombination checkpoint blocks meiotic cell cycle progression in response to synapsis and/or recombination defects to prevent aberrant chromosome segregation. The evolutionarily-conserved budding yeast Pch2 TRIP13 AAA+ ATPase participates in this pathway by supporting phosphorylation of the Hop1 HORMAD adaptor at T318. In the wild type, Pch2 localizes to synapsed chromosomes and to the unsynapsed rDNA region (nucleolus), excluding Hop1. In contrast, in synaptonemal complex (SC)-defective zip1Δ mutants, which undergo checkpoint activation, Pch2 is detected only on the nucleolus. Alterations in some epigenetic marks that lead to Pch2 dispersion from the nucleolus suppress zip1Δ-induced checkpoint arrest. These observations have led to the notion that Pch2 nucleolar localization could be important for the meiotic recombination checkpoint. Here we investigate how Pch2 chromosomal distribution impacts on checkpoint function. We have generated and characterized several mutations that alter Pch2 localization pattern resulting in aberrant Hop1 distribution and compromised meiotic checkpoint response. Besides the AAA+ signature, we have identified a basic motif in the extended N-terminal domain critical for Pch2's checkpoint function and localization. We have also examined the functional relevance of the described Orc1-Pch2 interaction. Both proteins colocalize in the rDNA, and Orc1 depletion during meiotic prophase prevents Pch2 targeting to the rDNA allowing unwanted Hop1 accumulation on this region. However, Pch2 association with SC components remains intact in the absence of Orc1. We finally show that checkpoint activation is not affected by the lack of Orc1 demonstrating that, in contrast to previous hypotheses, nucleolar localization of Pch2 is actually dispensable for the meiotic checkpoint.3

show abstract

“…In this work, we have used the zip1 mutant of the budding yeast Saccharomyces cerevisiae as a genetic tool to activate the MRC. Zip1 is a major structural component of the SC central region and ZIP1 deletion impairs synapsis and crossover (CO) recombination (Dong and Roeder 2000;Borner et al 2004;Voelkel-Meiman et al 2015); as a consequence, the zip1 mutant experiences a significant MRC-dependent delay in the prophase to meiosis I transition (Herruzo et al 2016). The zip1-induced defects are detected by the Mec1-Ddc2 (ATR-ATRIP) complex, resulting in phosphorylation of the Hop1 checkpoint adaptor at several residues, including T318 (Carballo et al 2008;Refolio et al 2011;Penedos et al 2015).…”

mentioning

confidence: 99%

Functional Impact of the H2A.Z Histone Variant During Meiosis in Saccharomyces cerevisiae

et al. 2018

Self Cite

View full text Add to dashboard Cite

Among the collection of chromatin modifications that influence its function and structure, the substitution of canonical histones by the so-called histone variants is one of the most prominent actions. Since crucial meiotic transactions are modulated by chromatin, here we investigate the functional contribution of the H2A.Z histone variant during both unperturbed meiosis and upon challenging conditions where the meiotic recombination checkpoint is triggered in budding yeast by the absence of the synaptonemal complex component Zip1 We have found that H2A.Z localizes to meiotic chromosomes in an SWR1-dependent manner. Although meiotic recombination is not substantially altered, the mutant (lacking H2A.Z) shows inefficient meiotic progression, impaired sporulation, and reduced spore viability. These phenotypes are likely accounted for by the misregulation of meiotic gene expression landscape observed in In the mutant, the absence of H2A.Z results in a tighter meiotic arrest imposed by the meiotic recombination checkpoint. We have found that Mec1-dependent Hop1-T318 phosphorylation and the ensuing Mek1 activation are not significantly altered in; however, downstream checkpoint targets, such as the meiosis I-promoting factors Ndt80, Cdc5, and Clb1, are drastically downregulated. The study of the checkpoint response in has also allowed us to reveal the existence of an additional function of the Swe1 kinase, independent of CDK inhibitory phosphorylation, which is relevant to restrain meiotic cell cycle progression. In summary, our study shows that the H2A.Z histone variant impacts various aspects of meiotic development adding further insight into the relevance of chromatin dynamics for accurate gametogenesis.

show abstract

The Pch2 AAA+ ATPase promotes phosphorylation of the Hop1 meiotic checkpoint adaptor in response to synaptonemal complex defects

Cited by 48 publications

References 77 publications

Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1

Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1

Characterization of Pch2 localization determinants reveals a nucleolar-independent role in the meiotic recombination checkpoint

Functional Impact of the H2A.Z Histone Variant During Meiosis in Saccharomyces cerevisiae

Contact Info

Product

Resources

About