HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity

Ye, Qiaozhen; Lau, Rebecca; Mathews, Ian T.; Birkholz, Erica A.; Watrous, Jeramie D.; Azimi, Camillia S.; Pogliano, Joe; Jain, Mohit; Corbett, K.D.

doi:10.1016/j.molcel.2019.12.009

Cited by 137 publications

(171 citation statements)

References 55 publications

(85 reference statements)

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“…Revealing the biochemical basis of Pch2-recruitment to chromosomes, and understanding whether additional regulation drives the switch of Pch2 from ‘monomeric’ C-Hop1 to chromosome-associated C-Hop1 are questions that warrant investigation. Finally, the fact that two checkpoint cascades that respond to distinct chromosomal defects show analogous biochemical signaling logic raises fascinating questions regarding the evolutionary history and origin of these essential signaling pathways [71].…”

Section: Resultsmentioning

confidence: 99%

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

Raina

Vader

2020

Preprint

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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 ...

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Section: Resultsmentioning

confidence: 99%

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

Raina

Vader

2020

Preprint

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“…For instance, a cGAS (cyclic GMP-AMP synthase)-like enzyme in a bacterial defense module synthesizes a cyclic GMP-AMP in response to phage infection, which leads to membrane degradation by a phospholipase and cell death (122). A recent study also reported that a cGAS/DncV-like nucleotidyltransferase (CD-NTase) could synthesize cOA3 , which in turn could bind and activate NucC, a DNA nuclease (123). Thus, insights into the cOA signaling pathway in Type III CRISPR-Cas systems may reveal concepts that are broadly applicable to other cyclic nucleotide-based antiphage signaling systems in prokaryotes.…”

Section: Comparison Of Type III Crispr-cas Systems With Other Nucleotmentioning

confidence: 99%

Chemistry of Class 1 CRISPR-Cas effectors: Binding, editing, and regulation

Liu

Doudna

2020

Journal of Biological Chemistry

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Among the multiple antiviral defense mechanisms found in prokaryotes, CRISPR-Cas systems stand out as the only known RNA-programmed pathways for detecting and destroying bacteriophages and plasmids. Class 1 CRISPR-Cas systems, the most widespread and diverse of these adaptive immune systems, use an RNA-guided multi-protein complex to find foreign nucleic acids and trigger their destruction. In this review, we describe how these multisubunit complexes target and cleave DNA and RNA, and how regulatory molecules control their activities. We also highlight similarities and differences to Class 2 CRISPR-Cas systems, which use a single-protein effector, as well as other types of bacterial and eukaryotic immune systems. We summarize current applications of the Class 1 CRISPR-Cas systems for DNA/RNA modification, control of gene expression, and nucleic acid detection.

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“…The importance of cyclic nucleotide signalling in prokaryote anti-viral defence systems is an emerging paradigm. Examples include cA4 and cA6 for type III CRISPR (5,6), cA3 for the HORMA-DncV-NucC system (24,25) and a variety of cyclic dinucleotides synthesised by diverse CBASS enzymes (26,27). Viruses have a clear imperative to degrade these molecules and circumvent immunity, but it is increasing apparent that cellular immune systems also need a mechanism to turnover these second messengers if they are to prevent runaway toxicity and cell death (13).…”

Section: Discussionmentioning

confidence: 99%

Fuse to defuse: a self-limiting ribonuclease-ring nuclease fusion for type III CRISPR defence

Samolygo

Athukoralage

Graham

et al. 2020

Preprint

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AbstractType III CRISPR systems synthesise cyclic oligoadenylate (cOA) second messengers in response to viral infection of bacteria and archaea, potentiating an immune response by binding and activating ancillary effector nucleases such as Csx1. As these effectors are not specific for invading nucleic acids, a prolonged activation can result in cell dormancy or death. To avoid this fate, some archaeal species encode a specialised ring nuclease enzyme (Crn1) to degrade cyclic tetra-adenylate (cA4) and deactivate the ancillary nucleases. Some archaeal viruses and bacteriophage encode a potent ring nuclease anti-CRISPR, AcrIII-1, to rapidly degrade cA4 and neutralise immunity. Homologues of this enzyme (named Crn2) exist in type III CRISPR systems but are uncharacterised. Here we describe an unusual fusion between cA4-activated CRISPR ribonuclease (Csx1) and a cA4-degrading ring nuclease (Crn2) from Marinitoga piezophila. The protein has two binding sites that compete for the cA4 ligand, a canonical cA4-activated ribonuclease activity in the Csx1 domain and a potent cA4 ring nuclease activity in the C-terminal Crn2 domain. The activities of the two constituent enzymes in the fusion protein cooperate to ensure a robust but time-limited cOA-activated ribonuclease activity that is finely tuned to cA4 levels as a second messenger of infection.

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HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity

Cited by 137 publications

References 55 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

Chemistry of Class 1 CRISPR-Cas effectors: Binding, editing, and regulation

Fuse to defuse: a self-limiting ribonuclease-ring nuclease fusion for type III CRISPR defence

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