Система защиты BREX из Escherichia coli HS и ее вирусные ингибиторы/BREX Defence System from Escherichia coli HS and its Virus-Encoded Inhibitor тема диссертации и автореферата по ВАК РФ 03.01.03, кандидат наук Исаев Артём Борисович

• Исаев Артём Борисович
• кандидат наук
• 2022

Оглавление диссертации кандидат наук Исаев Артём Борисович

Table of Contents

Abstract

Publications

Conferences

Acknowledgements

Table of Contents

Abbreviations

Chapter 1. Literature Review

1.1 Introduction

1.2 The simplest way of protection - to avoid recognition

Role of extracellular matrix (ECM) and outer membrane vesicles (OMV)

Receptors alterations

1.3 Small molecules and phage defence

Direct role in defence

Viperins and chain termination nucleotides

Regulatory role

1.4 Phage genome entry inhibition

1.5 DNA modification-based immunity systems

Classical R-M systems

Phage growth limitation (Pgl) system

BacteRiophage Exclusion (BREX) systems

Defence Island Systems Associated with Restriction-Modification (DISARM)

7-Deazapurine in DNA (DPD) systems

Phosphorothioate (PT) modification-based systems

1.6 CRISPR-Cas adaptive immunity systems

Diversity of CRISPR interference mechanisms

CRISPR Adaptation

1.7 Argonaute-mediated interference

1.8 Induced cell dormancy or suicide - Abortive Infection (Abi) and Toxin-Antitoxin (TA) systems

Abi systems

Toxin-Antitoxin (TA) based defence

Retrons as immunity systems

Cyclic-Oligonucleotide-Based Anti-Phage Signalling Systems (CBASS)

1.9 Prophage-mediated defence

1.10 Phage parasites - molecular piracy of the PICIs and PLEs

PICI

PLE

1.11 Systems with plausible novel mechanisms

1.12 Conclusions

Chapter 2. Project Rationale and Objectives

Chapter 3. Materials and Methods

3.1 Buffers

3.2 Bacterial strains, phages and plasmids

3.3 Bacterial and phage propagation

3.4 Phage titer determination and efficiency of plating (EOP) assay

3.5 Phage infection experiments

3.6 One-step growth curve assay

3.7 Efficiency of phage adsorption assay

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.8 Efficiency of phage DNA injection - potassium efflux assay

.9 Verification of phage X modification status

.10 Restriction endonuclease activity detection in cell lysates

.11 Molecular cloning

.12 Introduction of novel BREX sites in T7 genome

.13 DNA electrophoresis in agarose gel

.14 Preparation of electrocompetent cells

.15 Preparation of chemocompetent cells

.16 Competent cells transformation

.17 DNA purification

.18 ElectroMobility Shift Assay (EMSA)

.19 Southern Blot

.20 Transformation Efficiency Assay with M13 phage

.21 Next Generation gDNA sequencing and data analysis

.22 Sequencing of total DNA purified from T7-infected cells

.23 Strep-Seq analysis of BrxX binding to T7 DNA

.24 Protein purification and pull-down assay

.25 Polyacrylamide gel electrophoresis (PAGE)

.26 Protein identification with mass-spectrometry analysis

.27 Gel filtration

.28 In vitro biochemical activity assays

.29 In vitro ATPase activity assay

.30 In vitro SAM cleavage reaction

.31 HPLC separation of SAM and MTA

pter 4. Results and discussion

4.1 Overview of E. coli HS Type I BREX system proteins and their predicted activities

4.2 BREX proteins exist in a form of multicomponent complexes in vivo

4.3 BREX protects against diverse dsDNA phages

4.4 BREX inhibits early stages of the viral life cycle

4.5 Importance of BREX sites mutual orientation for defence

4.6 BREX defence is inhibited by phage T7 DNA mimic Ocr

Productive infection of BREX culture by phage T7 requires the presence of intact 0.3 gene

Ocr expression from plasmid shuts off the BREX defence

Ocr directly interacts with methyltransferase BrxX

Ocr decreases BREX methylation

4.7 BREX defence is SAM-dependent and is suppressed by phage T3 SAM lyase

Phage T3 overcomes BREX protection

Expression of T3 SAMase shuts off BREX defence

The anti-BREX activity of T3 SAMase is not associated with inhibition of methylation

Catalytically-deficient SAMase mutants retain anti-restriction activity

T3 SAMase binds to the host SAM synthase MetK and inhibits SAM synthesis

4.8 Expanding the network of interactions between defence systems and anti-restriction proteins

Chapter 5. Model of BREX defence and conclusions

Literature Citations

Supplementary Materials

Введение диссертации (часть автореферата) на тему «Система защиты BREX из Escherichia coli HS и ее вирусные ингибиторы/BREX Defence System from Escherichia coli HS and its Virus-Encoded Inhibitor»

Abstract

BREX is a superfamily of recently described phage defence systems that can be found in more than 10% of bacterial and archaeal genomes. Similar to classical Restriction-Modification systems BREX encodes methyltransferase and methylates the cell's own genome to discriminate it from incoming viral or plasmid DNA. However, BREX lacks an obvious restriction module and the set of biochemical activities predicted for BREX proteins (ATPase, alkaline phosphatase, Lon-like protease) is not characteristic for any defence system known. This work describes the Type I BREX defence system from E. coli HS, aiming to decipher how it interferes with viral propagation. It is shown that BREX does not prevent adsorption and injection stages, however, inhibits viral DNA accumulation inside infected cells. BREX system proteins interact with each other and form complexes (BrxBCXZ) that to a certain extent resemble complexes of heterooligomeric Type I/III R-M systems. Similar to these systems, the relative orientation of BREX sites in the viral DNA might be important for the efficiency of defence.

It was studied how certain phages overcome BREX protection, which led to the discovery of the first anti-BREX proteins. Phage T7 DNA-mimic Ocr - a well-known inhibitor of Type I R-M systems - was shown to be competent in shutting off BREX defence and affecting BREX methylation. BrxX methyltransferase appeared to be a target of Ocr anti-BREX activity. Another anti-BREX discovered in this work - phage T3 SAM Lyase, also known to be active against Type I R-M systems. This enzyme cleaves SAM - an important co-factor of R-M I restriction complexes. Results of this work suggest that SAM is required for BREX activity not only as a donor of methyl groups for methylation but also as a co-factor at the defence stage. An additional mechanism was discovered for T3 SAMase that likely contributes to its anti-restriction activity - SAMase is able to bind SAM synthase (MetK) and thus, in addition to direct enzymatic cleavage, depletes SAM pool through inhibition of its synthesis. Cloning and screening of the large collection of anti-restriction proteins allowed to identify phage P1 DarA as another anti-BREX, as well as to demonstrate that certain anti-restriction proteins can simultaneously downregulate Type IE CRISPR-Cas activity.

Publications

1. Gordeeva J., Morozova N., Sierro N., Isaev A., Sinkunas T., Tsvetkova K., Matlashov M., Truncaite L., Morgan R.D., Ivanov N.V., Siksnys V., Zeng L., Severinov K. BREX system of Escherichia coli distinguishes self from non-self by methylation of a specific DNA site. Nucleic Acids Research, Vol. 47(1), p.253-265, 2019

2. Isaev A., Drobiazko, A., Sierro, N., Gordeeva, J., Yosef, I., Qimron, U., Ivanov NV., Severinov, K. (2020). Phage T7 DNA mimic protein Ocr is a potent inhibitor of BREX defence. Nucleic Acids Research., Vol. 48(1), p.5397-5406, 2020

3. Isaev A., Musharova, O., Severinov, K. (2021). Microbial arsenal of antiviral defences -Part I. Biochemistry (Moscow), 86, 319-337, 2021.

4. Isaev A., Musharova, O., Severinov, K. (2021). Microbial arsenal of antiviral defences -Part II. Biochemistry (Moscow), 86, 449-470, 2021

Conferences

1. Isaev A.B., Gordeeva J.M., Tsvetkova K. M., Matlashov M. E., Severinov K. V. Insights from Study of BREX - Novel Bacterial Defence System. Molecular Genetics of Bacteria and Phages Meeting, Wisconsin, Madison, USA, 2018. poster presentation

2. Isaev A.B., Gordeeva J.M., Tsvetkova K. M., Matlashov M. E., Severinov K. V. Characterization of phage defence system BREX from Escherichia coli HS. Bacteriophage in Medicine, Food & Biotechnology, Oxford, UK, 2018. oral presentation

3. Isaev A., Drobiazko A.M., Gordeeva J., Severinov K. DNA mimic protein Ocr from phage T7 is a potent inhibitor of BREX defense system. CRISPR-2019, Quebec, Canada, 2019. poster presentation

4. Isaev A., Drobiazko A.M., Gordeeva J., Severinov K. DNA mimic protein Ocr from phage T7 is a potent inhibitor of BREX defense system. 3rd International Conference on CRISPR Technologies, Wurzburg, Germany, 2019. poster presentation

5. Isaev A., Drobiazko A.M., Gordeeva J., Severinov K. DNA mimic protein Ocr from phage T7 is a potent inhibitor of BREX defense system. Global Young Scientists Summit 2020, Singapore, 2020. poster presentation

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