It is unclear how important CRISPR-Cas systems are for protecting natural populations of bacteria against infections by mobile genetic elements

Westra, Edze R.; Levin, Bruce R

doi:10.1073/pnas.1915966117

Cited by 39 publications

(49 citation statements)

References 149 publications

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“…Although there is some available information on possible trade-offs between the replication rate and natural mortality of microorganisms and the size of the CRISPR system [ 16 , 46 ], these remain poorly understood overall. We should also admit that CRISPR is not the only mechanism of bacterial immunity and there are several other means to mount resistance against phages, for example as phase variation, and others [ 27 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…orphan arrays, loss of cas genes, decay in CRISPR repeats), so the cell will not able to acquire and actively uptake novel spacers. [ 27 ] In our model, we always assume that all bacteria with CRISPR can actively use this machinery.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, we should highlight that the above mathematical model can also describe a more complicated scenario of the abortive infection mechanism of CRISPR. According to this mechanism, even for the perfect match of spacer, the phage would kill the infected bacteria but will get a reduced burst size [ 27 , 36 ]. In this case, instead of a single cell, our model will consider a group of neighbouring cells as a combined entity.…”

Section: Methodsmentioning

confidence: 99%

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Searching for fat tails in CRISPR-Cas systems: Data analysis and mathematical modeling

et al. 2021

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Understanding CRISPR-Cas systems—the adaptive defence mechanism that about half of bacterial species and most of archaea use to neutralise viral attacks—is important for explaining the biodiversity observed in the microbial world as well as for editing animal and plant genomes effectively. The CRISPR-Cas system learns from previous viral infections and integrates small pieces from phage genomes called spacers into the microbial genome. The resulting library of spacers collected in CRISPR arrays is then compared with the DNA of potential invaders. One of the most intriguing and least well understood questions about CRISPR-Cas systems is the distribution of spacers across the microbial population. Here, using empirical data, we show that the global distribution of spacer numbers in CRISPR arrays across multiple biomes worldwide typically exhibits scale-invariant power law behaviour, and the standard deviation is greater than the sample mean. We develop a mathematical model of spacer loss and acquisition dynamics which fits observed data from almost four thousand metagenomes well. In analogy to the classical ‘rich-get-richer’ mechanism of power law emergence, the rate of spacer acquisition is proportional to the CRISPR array size, which allows a small proportion of CRISPRs within the population to possess a significant number of spacers. Our study provides an alternative explanation for the rarity of all-resistant super microbes in nature and why proliferation of phages can be highly successful despite the effectiveness of CRISPR-Cas systems.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Searching for fat tails in CRISPR-Cas systems: Data analysis and mathematical modeling

et al. 2021

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“…Immune reactions to invasions, infections and wounds are critical fitness traits in organisms, generally, and as the papers in this Special Issue illustrate, insects as well. While serious questions about the evolutionary ecology of microbial CRISPR-Cas immune systems remain open [ 1 ], the presence of these systems in bacteria and archaea and the differential expression of immune receptors in sponges (Order Porifera), the earliest extant metazoans [ 2 ], indicate immune mechanisms evolved very early in life. Immune reactions begin by recognition of pathogen-associated molecular patterns which launch biochemical signaling systems that activate insect cellular and humoral immune reactions.…”

Section: Introductionmentioning

confidence: 99%

Eicosanoid Signaling in Insect Immunology: New Genes and Unresolved Issues

Kim

Stanley

2021

Genes

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This paper is focused on eicosanoid signaling in insect immunology. We begin with eicosanoid biosynthesis through the actions of phospholipase A2, responsible for hydrolyzing the C18 polyunsaturated fatty acid, linoleic acid (18:2n-6), from cellular phospholipids, which is subsequently converted into arachidonic acid (AA; 20:4n-6) via elongases and desaturases. The synthesized AA is then oxygenated into one of three groups of eicosanoids, prostaglandins (PGs), epoxyeicosatrienoic acids (EETs) and lipoxygenase products. We mark the distinction between mammalian cyclooxygenases and insect peroxynectins, both of which convert AA into PGs. One PG, PGI2 (also called prostacyclin), is newly discovered in insects, as a negative regulator of immune reactions and a positive signal in juvenile development. Two new elements of insect PG biology are a PG dehydrogenase and a PG reductase, both of which enact necessary PG catabolism. EETs, which are produced from AA via cytochrome P450s, also act in immune signaling, acting as pro-inflammatory signals. Eicosanoids signal a wide range of cellular immune reactions to infections, invasions and wounding, including nodulation, cell spreading, hemocyte migration and releasing prophenoloxidase from oenocytoids, a class of lepidopteran hemocytes. We briefly review the relatively scant knowledge on insect PG receptors and note PGs also act in gut immunity and in humoral immunity. Detailed new information on PG actions in mosquito immunity against the malarial agent, Plasmodium berghei, has recently emerged and we treat this exciting new work. The new findings on eicosanoid actions in insect immunity have emerged from a very broad range of research at the genetic, cellular and organismal levels, all taking place at the international level.

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“…These comprise a DNA locus called ‘CRISPR’ (Clustered Regularly Interspaced Short Palindromic Repeats) and genes encoding ‘Cas’ (CRISPR associated) proteins, and sometimes additional non-Cas proteins. Comprehensive recent perspectives of CRISPR systems can be found in [ 1 , 2 , 3 ], and the references therein. Functional interaction and co-operation between CRISPR DNA and its transcribed RNA (crRNA) and Cas proteins generate immunity against future infection by the same or similar MGEs (CRISPR ‘Adaptation’) and destroy the MGE (CRISPR ‘Interference’).…”

Section: Introductionmentioning

confidence: 99%

A Tryptophan ‘Gate’ in the CRISPR-Cas3 Nuclease Controls ssDNA Entry into the Nuclease Site, That When Removed Results in Nuclease Hyperactivity

Liu

Matošević

Mitić

et al. 2021

IJMS

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Cas3 is a ssDNA-targeting nuclease-helicase essential for class 1 prokaryotic CRISPR immunity systems, which has been utilized for genome editing in human cells. Cas3-DNA crystal structures show that ssDNA follows a pathway from helicase domains into a HD-nuclease active site, requiring protein conformational flexibility during DNA translocation. In genetic studies, we had noted that the efficacy of Cas3 in CRISPR immunity was drastically reduced when temperature was increased from 30 °C to 37 °C, caused by an unknown mechanism. Here, using E. coli Cas3 proteins, we show that reduced nuclease activity at higher temperature corresponds with measurable changes in protein structure. This effect of temperature on Cas3 was alleviated by changing a single highly conserved tryptophan residue (Trp-406) into an alanine. This Cas3W406A protein is a hyperactive nuclease that functions independently from temperature and from the interference effector module Cascade. Trp-406 is situated at the interface of Cas3 HD and RecA1 domains that is important for maneuvering DNA into the nuclease active site. Molecular dynamics simulations based on the experimental data showed temperature-induced changes in positioning of Trp-406 that either blocked or cleared the ssDNA pathway. We propose that Trp-406 forms a ‘gate’ for controlling Cas3 nuclease activity via access of ssDNA to the nuclease active site. The effect of temperature in these experiments may indicate allosteric control of Cas3 nuclease activity caused by changes in protein conformations. The hyperactive Cas3W406A protein may offer improved Cas3-based genetic editing in human cells.

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It is unclear how important CRISPR-Cas systems are for protecting natural populations of bacteria against infections by mobile genetic elements

Cited by 39 publications

References 149 publications

Searching for fat tails in CRISPR-Cas systems: Data analysis and mathematical modeling

Searching for fat tails in CRISPR-Cas systems: Data analysis and mathematical modeling

Eicosanoid Signaling in Insect Immunology: New Genes and Unresolved Issues

A Tryptophan ‘Gate’ in the CRISPR-Cas3 Nuclease Controls ssDNA Entry into the Nuclease Site, That When Removed Results in Nuclease Hyperactivity

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