Phage-Encoded TelN Inhibits Mre11-Rad50 to Protect Hairpin Telomeres
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Abstract
The ends of linear chromosomes require protection from host repair machinery that otherwise will mistake them for damaged DNA. The E. coli bacteriophage N15 harbors a linear genome with covalently closed hairpin ends formed by the phage-encoded telomere resolvase TelN. The double-strand break repair complex Mre11-Rad50 (MR) specifically targets DNA termini, posing a direct threat to N15 genome integrity, yet how hairpin telomeres evade host nuclease degradation in bacteria remains unknown. Here, we demonstrate that TelN is essential and sufficient to protect hairpin telomeres from MR processing in E. coli . Using a combination of genetic and biochemical approaches, we show that this protective function requires both TelN sequence-specific DNA binding and species-specific protein- protein interactions. Notably, we found that protection is independent of TelN’s resolution activity and does not require the C-terminal domain of TelN. Our findings reveal a potentially broad mechanism of telomere protection, providing insights into a conserved regulation of MR activity at chromosome ends across the tree of life.
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Reply to the reviewers
We appreciate the constructive and supportive feedback on our manuscript. All three reviewers acknowledged the significance and novelty of our work on bacterial telomere protection. In response to their suggestions, we have conducted the requested experiments and revised the manuscript accordingly. These changes have enhanced the rigor of our study and clarified our interpretations and explanations.
Moreover, we characterized an additional truncation mutant of TelN (TelN Δ445–631), which lacks the two C-terminal domains. Despite this deletion, the mutant retained protection activity (Supplementary Figure S4B), indicating that the remaining regions of …
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Reply to the reviewers
We appreciate the constructive and supportive feedback on our manuscript. All three reviewers acknowledged the significance and novelty of our work on bacterial telomere protection. In response to their suggestions, we have conducted the requested experiments and revised the manuscript accordingly. These changes have enhanced the rigor of our study and clarified our interpretations and explanations.
Moreover, we characterized an additional truncation mutant of TelN (TelN Δ445–631), which lacks the two C-terminal domains. Despite this deletion, the mutant retained protection activity (Supplementary Figure S4B), indicating that the remaining regions of the protein are sufficient to confer efficient protection in this assay.
Finally, we removed three sequence alignments (previously Supplementary Figures S6A and S7), as we recognized that the high degree of sequence divergence could hinder proper alignment and potentially lead to misinterpretation.
Reviewer #1 (Evidence, reproducibility and clarity (Required)):
This study addresses how the bacterial telomere protein TelN protects telomere ends against the action of the Mre11-Rad50 nuclease (MR). This protection is essential for the stability of hairpin-ended linear plasmid and chromosomes in bacteria but had not been explored before. The authors demonstrate that TelN is necessary and sufficient to block MR-dependent DNA cleavage when bound to its specific telomere sequence. By combining elegant genetics and biochemical approaches, it convincingly shows that TelN-dependent inhibition likely involves a specific interaction between TelN and the MR complex. The manuscript is well written, easy to read and focused on the relevant information. The claims and the conclusions are supported by the data. There is no over-interpretation.
Comments:
- Figure 1B, unnormalized transformation efficiency would be useful to show in SI
The unnormalized* B. subtilis* transformation efficiency has now been added as new figure panel S1B.
- Figures 2B, 2C, 3C, 3D, 4C, 5A and 5B: quantification of independent experiments should be added
While these DNA protection experiments show a clearly reproducible pattern of DNA degradation, the exact response to TelN titration varies somewhat between experimental replicates. We initially included the quantification of remaining full-length DNA because the corresponding band is hard to discern in the gel image due to pixel saturation. However, we realize now that this may mislead readers to think that the degradation occurs always with the exact same dosage response.
To avoid this, we have decided to remove the quantification and instead show the relevant part of the gel also at higher contrast to better visualize the loss of full-length DNA due to DNA degradation. In addition, we have included replicate experiments carried out at the same MR concentration (125 nM M₂R₂) or at higher concentration (500 nM M₂R₂) in the supplementary material. These examples demonstrate the general reproducibility of the assay.
**Referee cross-commenting**
Perfect for me. It seems that there is a consensus.
Reviewer #1 (Significance (Required)):
This pioneering study provides a very strong basis for a new understanding of telomeres in bacteria and offers fascinating evolutionary perspectives when compared to similar mechanisms active at telomeres in eukaryotic cells.
Reviewer #2 (Evidence, reproducibility and clarity (Required)):
The paper is well-presented and well-written throughout. The paper shows convincingly that TelN protects hairpin DNA ends from the activity of SbcCD, presumably providing a protection mechanism for N15 phage DNA in vivo. Furthermore, this protection activity is shown not to require the catalytic (resolvase) activity of TelN, nor its poorly characterised C-terminal domain. The paper also suggests that this inhibition acts both at the level of competition for the DNA hairpin end and at the level of a direct protein:protein interaction between TelN and MR. An (acknowledged) weakness is that there is no real insight into the protein:protein interaction suggested by the experiments shown in Figure 5. Ideally, the protein:protein interaction interface would be identified and mutations in this interface would be shown to reduce hairpin protection.
Specific comments/questions
(1) What pathway (in vivo) leads to inactivation of linear hairpin DNA - one suspects that cleavage by SbcCD at the hairpins is probably not the full story. Presumably SbcCD cleavage facilitates further processing by other long range resection systems such as RecBCD, Exo1, RecQ/J etc. Would it be appropriate to view the hairpin as an adaption to protect against these nucleases, which then must be complemented with a mechanism to suppress SbcCD?
The reviewer's suggestion that hairpin ends represent a first layer of adaptation against nucleolytic processing is compelling. Hairpin structures inherently resist many exonucleases due to their covalently closed nature (absence of free 3’ or 5’ ends) but remain vulnerable to MR processing (Connelly et al, 1998, 1999; Saathoff et al, 2018). This creates a scenario where effective telomere protection requires both the structural barrier provided by the hairpin and an active mechanism to suppress MR activity. We have added this perspective to the relevant paragraph in the discussion.
(2) Section starting "Direct inhibition of MR by TelN in vitro". What is the word direct supposed to convey here? To me it suggests that the inhibition is via direct interaction of TelN with MR (rather than, for example, a result of competition for the hairpin DNA end) which is not shown here. Suggest either defining or removing the word direct. This point gains more importance considering that differentiating between inhibition mechanisms becomes a focus of later parts of the paper.
By "direct inhibition," we meant that TelN blocks MR nuclease activity without requiring additional cofactors, as demonstrated in this minimal reaction system containing only TelN, MR complex, DNA substrate, and ATP. To avoid ambiguity, we have reworded the corresponding headline and paragraph.
(3) Figure 2B - Why no control lane without MR? - this is a basic control to show that he degradation we are seeing in the absence of TelN is MR-dependent. Formally, as shown, the degradation could be caused by the ATP stock.
We have now included ATP-only control lanes (without MR complex), which show no substrate degradation, confirming that ATP stocks do not contain contaminating nucleases and that the observed degradation is indeed MR-dependent. These controls are included in the supplementary data (Figure S3A) along with additional replicate experiments. Notably, the dose-dependent protection observed at low TelN concentrations (where MR activity is not fully inhibited) provides additional evidence for the specificity of the MR-TelN interaction system, as non-specific nuclease contamination would result in complete substrate degradation regardless of TelN concentration.
(4) Why not use B. subtilis SbcCD for the species specificity experiment? Also, is it not surprising that TelN yielded zero protection against MRX given that the DNA sequence specificity experiments above suggest competition for DNA substrate is part of the inhibition mechanism?
We agree that this would be a great addition. We attempted but were unable to purify active *B. subtilis *SbcCD protein despite multiple attempts. The yeast MRX experiment serves the same purpose of demonstrating species specificity and represents a more evolutionarily distant comparison, which strengthens our conclusions about bacterial-specific inhibition.
(5) If the authors felt it appropriate, I thought there was scope for further discussion/introductory material. There are strong parallels here with mechanisms used by phage to protect themselves from the activities of RecBCD, which include both proteins that protect DNA ends like T4 gene 2, we well as proteins that bind directly to RecBCD to inactivate it like lambda Gam. As such, the work here will appeal as much to those interested in bacterial defence systems / phage:host interactions as it does to those interested in telomere biology. Especially significant is the inhibition of DNA end processing factors by lambda Gam since this protein is reported to interact with both RecBCD and SbcCD (PMID: 2531105).
We agree that there are obvious parallels between lambda Gam and TelN as counter-defence factors. This was likely largely missed in previous work because the telomere resolution activity of TelN masked its function in counter-defence. We have added a statement on this matter at the end of the discussion.
(6) Just a gripe really: it seems to be 'de rigeur' at the moment to re-name bacterial proteins for their human orthologues, presumably to elevate the perceived importance of the work(?), but it is not a practice I think is terribly helpful as it causes issues when searching literature. Minimally it would be great if the authors could ensure they add SbcCD as a keyword for search purposes.
We appreciate the reviewer's concern about nomenclature inconsistencies in the literature. We have chosen MR over SbcCD as a more generic term that covers eukaryotes, archaea and lately also bacteria and will hopefully contribute to a more consistent terminology in the literature across the domains of life in the future. Our choice to use "Mre11-Rad50" (MR) for the E. coli SbcCD complex is also consistent with prominent recent publications (Käshammer et al., 2019; Gut et al., 2022), explicitly referring to the E. coli system as "Mre11-Rad50" while acknowledging the bacterial designation. To link to previous literature, we made sure that both "SbcCD" and "Mre11-Rad50" are mentioned in the abstract. And, as suggested, we have now also added “SbcCD” to our keyword list to facilitate comprehensive literature searches.
**Referee cross-commenting**
I have nothing to add. The reviewers' comments are all broadly positive and consistent.
Reviewer #2 (Significance (Required):
This is an excellent paper unveiling a phage encoded "counter-defence" mechanism designed to protect phage DNA from degradation. It will be of special interest to those studying telomere biology of phage:host interactions.
Reviewer #3
The authors investigate how the N15 phage protelomerase TelN protects linear chromosomes that terminate in hairpin structures (a sort of telomere). In E. coli and B. subtilis cells, removal or truncation of telN reduces transformation/survival of linear DNA, whereas complementation with full-length or a catalytically inactive TelN restores viability, consistent with TelN playing a nonenzymatic capping function.
In vitro, TelN binds hairpin substrates with moderate affinity and protects them from the nuclease activity of the Mre11/Rad50 complex. The authors propose that TelN originated as an early, sequence specific barrier against MR mediated DNA end processing, establishing fundamental principles of telomere protection that persist from bacteria to eukaryotes.
Major comments:
The manuscript convincingly shows that TelN can functionally block the Mre11Rad50 (MR) nuclease on a hairpin DNA end in a sequence specific manner (suggesting a physical interaction), but it doesn't directly demonstrate this. A simple pull-down or equilibrium binding method would be useful in proving a physical interaction.
We agree that this would be a valuable addition to the study. We have made several attempts to detect direct interaction by co-immunoprecipitation. However, without success so far. We do not have sufficient material for equilibrium binding methods (yet).__ ____ __
The MR complex requires ATP hydrolysis for resection of DNA ends. It would be a nice addition to the manuscript if the effect of TelN of Rad50 ATPase activity was tested.
We have tested the effect of TelN on Rad50 ATPase activity and found no significant impact under our experimental conditions, possible in line with the lack of stable interaction.
The bar plot on Fig 3B indicates that the experiments are performed in triplicate. The statistical significance of the differences between conditions should be determined. The same general comment could be made regarding the quantification of the polyacrylamide gels - how reproducible are these values?
We performed paired t-test analysis for the following figures and now indicate the p-values wherever significant (below 0.05): Figures 1D, 1E, 3B, 4B and S4B. We used paired t-tests to generally compare linear vs circular plasmid transformation efficiency for each condition. In Figure 4B, which included two different linear DNA constructs, we compared the two linear DNA constructs directly to each other. [Given that our experimental design included multiple control conditions with known expected outcomes to validate assay performance, rather than many independent exploratory comparisons, we report uncorrected p-values as the primary analysis. The inclusion of multiple controls with predictable outcomes reduces the likelihood of false positive interpretations.]
As stated in response to reviewer 1, while the exact values for the DNA degradation profile vary somewhat between experiments (likely due to variations in band quantification – see also response to comment below), the general trends are robust as for example indicated by similar experiments performed with higher MR concentration (500 nM instead of 125 nM M₂R₂ concentrations for all TelN variants) demonstrating reproducibility across different conditions. For Figure 5, however, we are unable to provide additional repeat experiments due to limitations in reagent availability. Considering the robust effect seen with Ec MR controls and the presence of multiple samples in the dilution series, we are nevertheless confident about the conclusion.
Minor comments:
A better explanation of how the gels were quantified should be provided. Were the products included in the analysis, or was it just the decrease in the substrate band that was measured?
As also stated above, we have removed the band quantification and instead show the bands also at different contrast settings.
In our original approach, gel band quantification was performed using ImageQuant TL software (version 8.2.0, GE Healthcare). For each gel, individual lanes were defined using either fixed-width boundaries (95-103 pixels) or automatic edge detection, depending on the gel quality and band definition. Band volumes were calculated using rolling ball background subtraction (radius 180 pixels) with automatic band detection. Substrate degradation was assessed by measuring the integrated density (volume) of the remaining full-length (or near full-length) substrate bands under different treatment conditions. The band volume values were plotted directly to compare substrate levels across treatment groups.
We now present the data as two gel panels: an exposure showing the full reaction profile, and another exposure focusing on the substrate bands to clearly demonstrate dose-dependent protection. Additional replicate experiments including ATP-only controls (confirming no contamination from ATP stocks) and experiments at 500 nM M₂R₂ concentrations, are provided in the supplementary data. This approach provides more direct visualization of the biological phenomenon with comprehensive control validation.
I felt like the Results jump rather abruptly from B. subtilis chromosome assays to E. coli plasmid experiments. Maybe the addition of a few linking sentences would improve this transition.
Upon re-reading the manuscript we agree with this assertion and have added further information to provide a smoother transition.
A comment on the stoichiometry of TelN and genome ends during phage replication would be useful.
Our in vitro data suggest that effective protection can be achieved at relatively low TelN:DNA ratios in vitro, consistent with the notion of formation of stable, protective nucleoprotein structures. We unfortunately do not currently have information on the copy number of TelN per cell or per hairpin end. It is not easy to obtain reliable values for these numbers. However, we can speculate that multiple TelN proteins are present due to the presence of three copies of a DNA sequence motif (binding to CTD1) in each telomeric DNA, consistent with the formation of stable, protective nucleoprotein structures.
Reviewer #3 (Significance (Required)):
General assessment:
Strengths: A nice combination of genetics and biochemistry convincingly demonstrates that TelN protects linear chromosomes/replicons from MR-dependent degradation independent of its cleavage-ligase activity. It does this by binding to the hairpin DNA ends in a sequence specific fashion and the species specificity suggests a direct physical interaction, which likely inhibits the nuclease activity of the MR complex
Limitations: The lack of characterization of the putative physical interaction between TelN and the MR complex is considered a weakness.
Advance: The manuscript fills in a mechanistic gap between protelomerase-mediated telomere formation and maintenance by demonstrating a protective/capping role. This is the first quantitative analysis of DNA-end protection from MR nuclease activity by TelN.
Audience: Readers interested in bacterial chromosome biology, DNA repair, the parallels to eukaryotic shelterin will be interesting to the broader telomere and genome stability communities.
-
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #3
Evidence, reproducibility and clarity
Summary:
The authors investigate how the N15 phage protelomerase TelN protects linear chromosomes that terminate in hairpin structures (a sort of telomere). In E. coli and B. subtilis cells, removal or truncation of telN reduces transformation/survival of linear DNA, whereas complementation with full‑length or a catalytically inactive TelN restores viability, consistent with TelN playing a non‑enzymatic capping function.
In vitro, TelN binds hairpin substrates with moderate affinity and protects them from the nuclease activity of the Mre11/Rad50 complex. The authors propose that TelN originated as an early, sequence‑specific …
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #3
Evidence, reproducibility and clarity
Summary:
The authors investigate how the N15 phage protelomerase TelN protects linear chromosomes that terminate in hairpin structures (a sort of telomere). In E. coli and B. subtilis cells, removal or truncation of telN reduces transformation/survival of linear DNA, whereas complementation with full‑length or a catalytically inactive TelN restores viability, consistent with TelN playing a non‑enzymatic capping function.
In vitro, TelN binds hairpin substrates with moderate affinity and protects them from the nuclease activity of the Mre11/Rad50 complex. The authors propose that TelN originated as an early, sequence‑specific barrier against MR‑mediated DNA end processing, establishing fundamental principles of telomere protection that persist from bacteria to eukaryotes.
Major comments:
The manuscript convincingly shows that TelN can functionally block the Mre11‑Rad50 (MR) nuclease on a hair‑pin DNA end in a sequence specific manner (suggesting a physical interaction), but it doesn't directly demonstrate this. A simple pull-down or equilibrium binding method would useful in proving a physical interaction.
The MR complex requires ATP hydrolysis for resection of DNA ends. It would be a nice addition to the manuscript if the effect of TelN of Rad50 ATPase activity was tested.
The bar plot on Fig 3B indicates that the experiments are performed in triplicate. The statistical significance of the differences between conditions should be determined. The same general comment could be made regarding the quantification of the polyacrylamide gels - how reproducible are these values?
Minor comments:
A better explanation of how the gels were quantified should be provided. Were the products included in the analysis, or was it just the decrease in the substrate band that was measured?
I felt like the Results jump rather abruptly from B. subtilis chromosome assays to E. coli plasmid experiments. Maybe the addition of a few linking sentences would improve this transition.
A comment on the stoichiometry of TelN and genome ends during phage replication would be useful.
Significance
General assessment:
Strengths: A nice combination of genetics and biochemistry convincingly demonstrates that TelN protects linear chromosomes/replicons from MR-dependent degradation independent of its cleavage-ligase activity. It does this by binding to the hairpin DNA ends in a sequence specific fashion and the species specificity suggests a direct physical interaction, which likely inhibits the nuclease activity of the MR complex
Limitations: The lack of characterization of the putative physical interaction between TelN and the MR complex is considered a weakness.
Advance: The manuscript fills in a mechanistic gap between protelomerase‑mediated telomere formation and maintenance by demonstrating a protective/capping role. This is the first quantitative analysis of DNA-end protection from MR nuclease activity by TelN.
Audience: Readers interested in bacterial chromosome biology, DNA repair, the parallels to eukaryotic shelterin will be interesting to the broader telomere and genome‑stability communities.
-
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #2
Evidence, reproducibility and clarity
The paper is well-presented and well-written throughout. The paper shows convincingly that TelN protects hairpin DNA ends from the activity of SbcCD, presumably providing a protection mechanism for N15 phage DNA in vivo. Furthermore, this protection activity is shown not to require the catalytic (resolvase) activity of TelN, nor its poorly characterised C-terminal domain. The paper also suggests that this inhibition acts both at the level of competition for the DNA hairpin end and at the level of a direct protein:protein interaction between TelN and MR. An (acknowledged) weakness is that there is no real insight into the …
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #2
Evidence, reproducibility and clarity
The paper is well-presented and well-written throughout. The paper shows convincingly that TelN protects hairpin DNA ends from the activity of SbcCD, presumably providing a protection mechanism for N15 phage DNA in vivo. Furthermore, this protection activity is shown not to require the catalytic (resolvase) activity of TelN, nor its poorly characterised C-terminal domain. The paper also suggests that this inhibition acts both at the level of competition for the DNA hairpin end and at the level of a direct protein:protein interaction between TelN and MR. An (acknowledged) weakness is that there is no real insight into the protein:protein interaction suggested by the experiments shown in Figure 5. Ideally, the protein:protein interaction interface would be identified and mutations in this interface would be shown to reduce hairpin protection.
Specific comments/questions
(1) What pathway (in vivo) leads to inactivation of linear hairpin DNA - one suspects that cleavage by SbcCD at the hairpins is probably not the full story. Presumably SbcCD cleavage facilitates further processing by other long range resection systems such as RecBCD, Exo1, RecQ/J etc. Would it be appropriate to view the hairpin as an adaption to protect against these nucleases, which then must be complemented with a mechanism to suppress SbcCD?
(2) Section starting "Direct inhibition of MR by TelN in vitro". What is the word direct supposed to convey here? To me it suggests that the inhibition is via direct interaction of TelN with MR (rather than, for example, a result of competition for the hairpin DNA end) which is not shown here. Suggest either defining or removing the word direct. This point gains more importance considering that differentiating between inhibition mechanisms becomes a focus of later parts of the paper.
(3) Figure 2B - Why no control lane without MR? - this is a basic control to show that he degradation we are seeing in the absence of TelN is MR-dependent. Formally, as shown, the degradation could be caused by the ATP stock.
(4) Why not use B. subtilis SbcCD for the species specificity experiment? Also, is it not surprising that TelN yielded zero protection against MRX given that the DNA sequence specificity experiments above suggest competition for DNA substrate is part of the inhibition mechanism?
(5) If the authors felt it appropriate, I thought there was scope for further discussion/introductory material. There are strong parallels here with mechanisms used by phage to protect themselves from the activities of RecBCD, which include both proteins that protect DNA ends like T4 gene 2, we well as proteins that bind directly to RecBCD to inactivate it like lambda Gam. As such, the work here will appeal as much to those interested in bacterial defence systems / phage:host interactions as it does to those interested in telomere biology. Especially significant is the inhibition of DNA end processing factors by lambda Gam since this protein is reported to interact with both RecBCD and SbcCD (PMID: 2531105).
(6) Just a gripe really: it seems to be 'de rigeur' at the moment to re-name bacterial proteins for their human orthologues, presumably to elevate the perceived importance of the work(?), but it is not a practice I think is terribly helpful as it causes issues when searching literature. Minimally it would be great if the authors could ensure they add SbcCD as a keyword for search purposes.
Referee cross-commenting
I have nothing to add. The reviewers comments are all broadly positive and and consistent.
Significance
This is an excellent paper unveiling a phage encoded "counter-defence" mechanism designed to protect phage DNA from degradation. It will be of special interest to those studying telomere biology of phage:host interactions.
-
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #1
Evidence, reproducibility and clarity
This study addresses how the bacterial telomere protein TelN protect telomere ends against the action of the Mre11-Rad50 nuclease (MR). This protection is essential for the stability of hairpin-ended linear plasmid and chromosomes in bacteria but had not been explored before. The authors demonstrates that TelN is necessary and sufficient to block MR-dependent DNA cleavage when bound to its specific telomere sequence. By combining elegant genetics and biochemical approaches, it convincingly shows that TelN-dependent inhibition likely involves a specific interaction between TelN and the MR complex. The manuscript is well written, easy …
Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.
Learn more at Review Commons
Referee #1
Evidence, reproducibility and clarity
This study addresses how the bacterial telomere protein TelN protect telomere ends against the action of the Mre11-Rad50 nuclease (MR). This protection is essential for the stability of hairpin-ended linear plasmid and chromosomes in bacteria but had not been explored before. The authors demonstrates that TelN is necessary and sufficient to block MR-dependent DNA cleavage when bound to its specific telomere sequence. By combining elegant genetics and biochemical approaches, it convincingly shows that TelN-dependent inhibition likely involves a specific interaction between TelN and the MR complex. The manuscript is well written, easy to read and focused on the relevant information. The claims and the conclusions are supported by the data. There is no over-interpretation.
Comments:
- Figure 1B, unnormalized transformation efficiency would be useful to show in SI
- Figures 2B, 2C, 3C, 3D, 4C, 5A and 5B: quantification of independent experiments should be added
Referee cross-commenting
Perfect for me. It seems that there is a consensus.
Significance
This pioneering study provides a very strong basis for a new understanding of telomeres in bacteria and offers fascinating evolutionary perspectives when compared to similar mechanisms active at telomeres in eukaryotic cells.
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