Системы рестрикции-модификации в Escherichia coli: механизмы стабилизации плазмид и защиты от бактериофагов (Restriction-modification systems in Escherichia coli: phage protection and plasmid stabilization mechanisms) тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Козлова Светлана Юрьевна

• Козлова Светлана Юрьевна
• кандидат наук
• 2025

Оглавление диссертации кандидат наук Козлова Светлана Юрьевна

Table of Contents

Chapter 1. Introduction

Chapter 2. Literature review

2.1. Restriction-modification systems overview

2.2. Type I RM systems

2.2.1. EcoKI, EcoAI, and EcoR124I Type I RM systems

2.3. Type II RM systems

2.3.1. Esp1396I, EcoRV, Eco29kI, and EcoRI Type II RM systems

2.4. Type III and Type IV RM systems

2.5. Regulation of RM systems expression and activity

2.6. Diverse functions in addition to phage protection

2.6.1. PSK studies

2.7. Cooperation with other cell systems

2.7.1. RecBCD

2.8. Conclusions for literature review

Chapter 3. Materials and Methods

3.1. Bacterial strains, phages and plasmids

3.2. Bacterial growth and phage propagation

3.3. CRISPR interference assay

3.4. The PSK assay

3.5. Plasmid stability assay

3.6. Phage plaquing (EOP) assay

3.7. Plasmid copy number and a relative expression of MTase or REase genes determination

3.8. Microscopy

3.9. Fluorescence intensity calibration

3.10. SOS response detection

3.11. Restriction of X phage DNA in cell-free extracts

3.12. Statistical analysis

3.13. Deriving a model of RM-based PSK

Chapter 4. Dependence of post-segregational killing mediated by Type II restriction-modification systems on the lifetime of restriction endonuclease effective activity

4.1. Introduction

4.2. Results and discussion

4.2.1. Type II restriction-modification systems stabilize plasmids

4.2.2. CRISPR-mediated loss of plasmids containing some Type II RM systems leads to PSK52

4.2.3. Cells losing RM systems plasmids that cause PSK undergo SOS response

4.2.4. The Esp1396I REase activity is short-lived

4.2.5. Mathematical modeling of PSK mediated by TA and RM systems

4.3. Concluding remarks

Chapter 5. Cells with stochastically increased methyltransferase to restriction endonuclease ratio provide an entry for bacteriophage into protected cell population

5.2. Results and discussion

5.2.1. The copy number of plasmids carrying an RM system affects the level of protection from phage infection

5.2.2. The influence of additional REase or MTase enzymes on protection from bacteriophage infection

5.2.3. The influence of PCN and additional expression of REase or MTase on bacteriophage X DNA degradation after infection of cells carrying the Esp1396I_fluo RM system

5.2.4. Determination of REase and MTase levels in productively infected bacteria

5.3. Concluding remarks

Chapter 6. The role of RecBCD in anti-phage defense and processing of DNA breaks generated by RM systems

6.2. Results and discussion

6.2.1. M13 bacteriophage-based model system allows studying the influence of RM sites number and direction

6.2.2. Protection by RM systems against M13 phage depends on RM sites number and direction

6.2.3. Protection level is affected by presence of the Chi site in M13 phage genome

6.2.4. Protection level is not affected by ArecA mutation but affected by ArecB/C/D mutations for the EcoA and EcoKI Type I RM systems

6.2.5. ArecB/C/D mutations affect plasmid copy number and M to R ratio for the EcoKI system

6.2.6. Defense and PCN for the EcoKI are partially restored when RecBCD components are expressed from complementing plasmids

6.3. Concluding remarks

Conclusions

Acknowledgements

List of abbreviations

Bibliography

Appendix A. Supplementary figures and tables

Введение диссертации (часть автореферата) на тему «Системы рестрикции-модификации в Escherichia coli: механизмы стабилизации плазмид и защиты от бактериофагов (Restriction-modification systems in Escherichia coli: phage protection and plasmid stabilization mechanisms)»

Chapter 1. Introduction

Research topic relevance. Bacteria have evolved numerous mechanisms to resist the constant assault of viruses (called bacteriophages, or phages) that can infect and kill them. One such strategy is restriction-modification (RM) systems. RM systems comprise a methyltransferase (MTase) that modifies cognate sequences in DNA, adding a methyl group to a base in the recognition site, and a restriction endonuclease (REase) that recognizes the same site as an MTase and cleaves DNA if this site is unmodified [1]. When phage DNA with non-modified recognition sites is injected into bacterial cell, REase binds and cleaves this DNA preventing the progression of the phage's life cycle. Thus, RM systems are considered a part of the innate immune response because they can provide defense against any phage, including ones that have never been encountered previously, as long as they harbor RM target sites.

In addition to the defensive role of RM systems, they contribute to many other biological processes. They can participate in epigenetic regulation of transcription, be involved in recombination and genome rearrangements, and play a role in the control of the evolution of prokaryotes and maintenance of species identity [2, 3, 4, 5, 6]. The most common Type II RM systems can act as "addiction modules" because they were shown to stabilize plasmids where they reside by killing the cells that lose this plasmid; a phenomenon called post-segregational killing (PSK) [7, 8]. Thus, RM systems might participate in persistence of plasmids which are responsible for dissemination of clinically important determinants such as antibiotic resistance.

The intracellular amounts/activity levels of the MTase and REase enzymes shall be tightly controlled because an imbalance can either lead to the autoimmunity and death of uninfected (excess REase activity) or modification of phage DNA and death of infected (excess MTase activity) cells. Indeed, diverse regulatory mechanisms, including antisense RNAs that modulate RM genes expression, MTases that competes with RNA polymerase, and C proteins that ensure optimal levels of transcription of the RM genes, have been described (reviewed in [9]). Though these mechanisms ensure homeostasis of RM gene expression, RM protection can be overcome by phages, as methyltransferases can erroneously modify incoming viral genomes before restriction occurs [10].

Despite potential autoimmunity and imperfect phage protection, RM systems are abundant and present in 80% of prokaryotic genomes [11]. They are rarely present in isolation but clusters with other protective systems into defense islands [12]. For example, RM and CRISPR-Cas systems can act synergistically against phages, and a restriction promotes spacer acquisition [13, 14]. Another system that was suggested to participate in phage defense and likely cooperate with RM systems is RecBCD, an enzyme with two contradictory activities: DNA breaks repair and degradation of linear double-stranded DNA. It was shown that phage X DNA is degraded by RecBCD if it was previously cleaved by

restriction enzyme [15]. However, there are no works to our knowledge where phages cannot complete replication cycle solely due to RecBCD activity. Instead, a recent study showed that none of 160 phages tested were destroyed by RecBCD [16]. Creating a phage model where the cooperation of RM and RecBCD activities can be studied directly could shed a light on this contradictory data.

Understanding the costs and benefits of bacterial RM systems in nature requires future studies that take into account the complexity of natural environments, as well as their regulation and the interactions of multiple defense mechanisms in the same host genome.

Research objectives. The main goal of this work was to characterize non-canonical (plasmid stabilization and PSK) and canonical (anti-phage defense) functions of the E. coli RM systems.

To achieve the goal of the dissertation, the following problems are addressed:

1. To create a physiological model for elimination of plasmids from bacterial cell;

2. To investigate the mechanisms of plasmid stabilization and PSK mediated by Type II RM systems;

3. To develop a mathematical model for RM-mediated PSK;

4. To demonstrate the influence of RM proteins ratio on phage protection and the rate of phage DNA degradation;

5. To create a phage model with controlled number of RM recognition sites;

6. To explore the cooperation between RecBCD and RM systems in the defense process.

Scientific novelty. This thesis presents a novel physiological model based on CRISPR-Cas

interference for synchronous and rapid elimination of plasmids from E. coli cells for PSK and related studies. We also present a mathematical model that shows that unlike the case of toxin-antitoxin-mediated PSK based on different stabilities of antitoxin and toxin moieties, the loss of an RM system induced PSK even when the RM enzymes have identical lifetimes.

We demonstrated at a single-cell level that bacterial population carrying an RM system is not homogenous in terms of MTase to REase ratio in individual cells. Here, cells with stochastically increased MTase to REase ratio at the time of the infection can serve as entry points for unmodified phage into protected bacterial populations, leading to productive infection.

We showed that RecBCD does not directly cooperate with RM systems in anti-phage protection in a simple model system (phage without its own recombination pathway). As a side result, we demonstrated for the first time that MTase to REase ratio for Type I RM systems may depend on the copy number of plasmids encoding them, similarly to Type II RM systems, thus affecting frequency rate of escaper phages emergence.

Theoretical and practical significance of the results. Apart from advancing the theoretical knowledge of the traditional and non-canonical functions of RM systems, we created two biological models that can be used in further studies. Moreover, since RM systems was shown to stabilize plasmids,

they can be used instead of antibiotic resistance genes in biotechnological processes that often operate with plasmid-based expression systems.

A phage model with constrained number of RM recognition sites in phage genome can be applied for further studies, e.g., interaction of RM systems with prokaryotic argonauts (pAgos) or other phage defense systems. It can be also expanded to other phages encoding their own recombination machineries or RecBCD inhibitors to study the role of RecBCD in processing of phage DNA in more complex conditions.

A fluorescent labeling of proteins used for RM systems can be used as an alternative to standard methods (e.g., western blot) for proteins quantification in individual cells.

Methodology and research methods. The methods of molecular biology (molecular cloning, manipulations with nucleic acids, PCRs, gel electrophoresis, etc.) and microbiology (bacteria and phages cultivation, plating, PSK and plaque assays, etc.) were used throughout. Fluorescence microscopy was used in Chapter 4 and 5. A mathematical modelling was performed for Chapter 4.

Main results submitted for the defense are the following:

1. CRISPR interference-based method allows efficient elimination of plasmids from the E. coli host while minimally perturbing cell physiology.

2. PSK mediated by the loss of Type II RM system depends on restriction endonuclease activity lifetime and is not observed when it is less than two replication cycles.

3. A shift in the MTase to REase ratio caused by overproduction of MTase or REase leads, respectively, to decreased or increased protection from phage infection.

4. Cells with transiently increased MTase to REase ratio at the time of infection serve as entry points for unmodified phage DNA into protected bacterial populations.

5. Direct relationship between the number of RM sites and phage defense rate was demonstrated for the Type I and II R-M systems.

6. RecBCD-mediated clearance of RM-generated phage DNA breaks was shown not to affect overall phage defense rate in a simple model system.

Validity of the obtained results. The obtained results are consistent with published peer-reviewed experimental and mathematical data. All experiments were performed in at least three independent biological replicates, demonstrating reproducibility under our conditions. Statistical tests, where applied, confirmed that obtained results are not attributable to random variation.

Publications. The main results of this thesis resulted in 2 publications in scientific journals indexed in Web of Science and Scopus systems:

1. Kozlova S., Morozova N., Ispolatov Y., Severinov K. Dependence of post-segregational killing mediated by Type II restriction-modification systems on the lifetime of restriction endonuclease effective activity //mBio. - 2024. - V. 15 - P. e01408. (Main author)

2. Kirillov A., Morozova N., Kozlova S., Polinovskaya V., Smirnov S., Khodorkovskii M., Zeng L., Ispolatov Y., Severinov K. Cells with stochastically increased methyltransferase to restriction endonuclease ratio provide an entry for bacteriophage into protected cell population //Nucleic Acids Research. - 2022. - V. 50 - №21. - P. 12355-12368. (Co-author)

The results of the thesis were presented at the following international conferences:

1. Kozlova S., Severinov K., Isaev A. The role of RecBCD in anti-phage defense and processing of DNA breaks generated by RM systems // Genomics, metagenomics and molecular biology of microorganisms (Russia, 2024).

2. Kozlova S., Morozova N., Severinov K. Post-segregational killing by CRISPR-Cas interference-induced plasmid loss in E. coli // EMBO Workshop "Bacterial morphogenesis, survival and virulence: Dynamic genomes & envelopes" (India, 2023)

3. Kozlova S., Morozova N., Severinov K. Investigation of bacterial addiction modules by CRISPR-Cas interference-based model system // FEMS Conference on Microbiology (Serbia, 2022)

Personal contribution of the author. All key experiments and model constructions (except for mathematical model) described in Chapters 4 and 6 were performed by the author of this thesis. For Chapter 5, the author participated in most experiments summarized in Figures 5.1 and 5.2 and performed additional experiments presented in Supplementary Materials of the published paper. The author prepared manuscripts and conference abstracts described above.

Structure and volume of the dissertation. The dissertation consists of 7 chapters, including an Introduction, Literature review, Materials and Methods, and Conclusions. The dissertation is 128 pages long, including 32 figures, 3 tables and 7 objects in Appendix. The list of references contains 242 titles.

The Introduction (Chapter 1) summarizes the main blind spots in the covered topics and sets the objectives of this thesis by formulating the research questions. Chapter 2 provides a literature review and explains the background necessary for understanding the following sections. Chapter 3 describes the materials and methods. The results obtained during the work on the thesis are presented in Chapters 4-6. Each Chapter consists of a short introduction to the topic, combined results and discussion, and concluding remarks. Chapter 4 is dedicated to non-canonical functions of Type II RM systems - plasmid stabilization and post-segregational cell killing - which are studied experimentally and mathematically. Chapter 5 demonstrates the importance of RM proteins balance in phage protection. Chapter 6 is about cooperation of RM systems and RecBCD system in phage defense. Chapter 7 summarizes the obtained results, their correspondence to the set goals, and provides directions for further research.

Заключение диссертации по теме «Другие cпециальности», Козлова Светлана Юрьевна

Conclusions

This thesis aimed to characterize non-canonical (plasmid stabilization and PSK) and canonical (anti-phage defense) functions of the E. coli RM systems. The main results are:

1. CRISPR interference-based method allows efficient elimination of plasmids from the E. coli host while minimally perturbing cell physiology and can be used to study PSK and related phenomena.

2. PSK mediated by the loss of Type II RM system depends on restriction endonuclease activity lifetime and is not observed when it is less than two replication cycles. A temporal delay built in Type II RM systems to prevent autoimmunity provides an accessibility window that leads to PSK of cells that lost an RM plasmid even when the lifetimes of RM enzymes are the same.

3. A shift in the MTase to REase ratio caused by overproduction of MTase or REase leads, respectively, to decreased or increased protection from phage infection, which was explained by direct measurements of half-lives of injected unmodified phage DNA. The production of additional REase reduces the average time needed for degradation of phage DNA thus enhancing the level of protection, while in cells with additional MTase, the average time needed for invading phage DNA degradation is increased, ultimately abolishing protection.

4. Cells with transiently increased MTase to REase ratio at the time of infection serve as entry points for unmodified phage DNA into protected bacterial populations. Stochastic variation in intracellular amounts of RM enzymes leads to increased susceptibility of individual cells to infection, and DNA of progeny phage of such infection events are modified, allowing the virus to take over the initially protected population of cells.

5. Direct relationship between the number of RM sites and phage defense rate was demonstrated for the Type I and II RM systems.

6. RecBCD-mediated clearance of RM-generated phage DNA breaks was shown not to affect overall phage defense rate in a simple model system.

There are several areas for further development of the work undertaken in this thesis. For PSK studies, we can modify RM proteins with peptide or fluorescent tags to monitor RM proteins dynamics upon plasmid loss. We can also track methylation status of the cell to understand where DNA breaks are started to appear. A similar idea is to map DNA breaks generated by RM systems during PSK, a method which is currently developed in our laboratory. The work can be expanded to other addiction systems, such as toxin-antitoxin (TA) or bacteriocin modules. Plasmid maintenance systems are of a high interest in biotechnology, where the most established systems for heterologous productions of proteins and chemicals are plasmid-based and often requires antibiotics for plasmid selection. While TA systems are already shown to stabilize expression plasmids in industry [241, 242], the use of RM systems for these

purposes can be even more efficient because they provide both plasmid stabilization and phage protection.

Although in our relatively simple model (phage without its own reparation machinery or RecBCD inhibitors) we did not demonstrate the role of RecBCD in phage DNA processing upon RM-mediated cleavage, we will continue to dig into this topic. We will use more complex phage models (e.g., X, T7 and T4 with or without RecBCD inhibitors and recombination/ligation machinery) and create a model of "inefficient" restriction of phage DNA. Here, inducible nucleases (I-SceI or Cas9) should be used for cleaving phage DNA at later stages of infection, e.g., when it is already replicating. We are also going to expand our model using prokaryotic argonauts (pAgos), DNA-guided DNA nucleases participating in phage defense. Recent works demonstrated that pAgos can acquire guides at doublestrand breaks [127, 139], which suggests the possibility of interplay between RM, RecBCD and pAgos, where RM and/or RecBCD activity creates the substrates for guide acquisition, triggering pAgo defense against phages.

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