Topological stress is responsible for the detrimental outcomes of head-on replication-transcription conflicts

Kevin S. Lang; Houra Merrikh

doi:10.1016/j.celrep.2021.108797

Topological stress is responsible for the detrimental outcomes of head-on replication-transcription conflicts

Kevin S. Lang, Houra Merrikh

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Conflicts between the replication and transcription machineries have profound effects on chromosome duplication, genome organization, and evolution across species. Head-on conflicts (lagging-strand genes) are significantly more detrimental than codirectional conflicts (leading-strand genes). The fundamental reason for this difference is unknown. Here, we report that topological stress significantly contributes to this difference. We find that head-on, but not codirectional, conflict resolution requires the relaxation of positive supercoils by the type II topoisomerases DNA gyrase and Topo IV, at least in the Gram-positive model bacterium Bacillus subtilis. Interestingly, our data suggest that after positive supercoil resolution, gyrase introduces excessive negative supercoils at head-on conflict regions, driving pervasive R-loop formation. Altogether, our results reveal a fundamental mechanistic difference between the two types of encounters, addressing a long-standing question in the field of replication-transcription conflicts.

Original language	English (US)
Article number	108797
Journal	Cell reports
Volume	34
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2021.108797
State	Published - Mar 2 2021
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Christopher Merrikh and the other members (past and present) of the Merrikh lab, as well as Neil Osheroff and Felipe Cortés Ledesma for helpful discussions. The authors would also like to thank Sara Mangiameli for revising the manuscript and Peter Graumann for sharing strains. This work was supported by National Institutes of Health awards DP2GM110773 and R01GM128191-02 to H.M., Research Royalty Funds from the University of Washington to H.M., the 5T32-AI055396-13 Bacterial Pathogenesis Training Grant ( University of Washington ) award to K.S.L., and the 1F32 AI140557-01 Ruth L. Kirschstein National Research Postdoctoral award to K.S.L. We would like to dedicate this paper to the late James Champoux, who discovered Top1 and discussed this project with us on various occasions during our time at the University of Washington.

Funding Information:
We would like to thank Christopher Merrikh and the other members (past and present) of the Merrikh lab, as well as Neil Osheroff and Felipe Cort?s Ledesma for helpful discussions. The authors would also like to thank Sara Mangiameli for revising the manuscript and Peter Graumann for sharing strains. This work was supported by National Institutes of Health awards DP2GM110773 and R01GM128191-02 to H.M. Research Royalty Funds from the University of Washington to H.M. the 5T32-AI055396-13 Bacterial Pathogenesis Training Grant (University of Washington) award to K.S.L. and the 1F32 AI140557-01 Ruth L. Kirschstein National Research Postdoctoral award to K.S.L. We would like to dedicate this paper to the late James Champoux, who discovered Top1 and discussed this project with us on various occasions during our time at the University of Washington. K.S.L. and H.M. designed and performed the experiments, analyzed the data, and wrote the paper. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Author(s)

Keywords

DNA supercoiling
R-loops
Replication-transcription conflicts
Type II topoisomerases

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10.1016/j.celrep.2021.108797

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title = "Topological stress is responsible for the detrimental outcomes of head-on replication-transcription conflicts",

abstract = "Conflicts between the replication and transcription machineries have profound effects on chromosome duplication, genome organization, and evolution across species. Head-on conflicts (lagging-strand genes) are significantly more detrimental than codirectional conflicts (leading-strand genes). The fundamental reason for this difference is unknown. Here, we report that topological stress significantly contributes to this difference. We find that head-on, but not codirectional, conflict resolution requires the relaxation of positive supercoils by the type II topoisomerases DNA gyrase and Topo IV, at least in the Gram-positive model bacterium Bacillus subtilis. Interestingly, our data suggest that after positive supercoil resolution, gyrase introduces excessive negative supercoils at head-on conflict regions, driving pervasive R-loop formation. Altogether, our results reveal a fundamental mechanistic difference between the two types of encounters, addressing a long-standing question in the field of replication-transcription conflicts.",

keywords = "DNA supercoiling, R-loops, Replication-transcription conflicts, Type II topoisomerases",

author = "Lang, {Kevin S.} and Houra Merrikh",

note = "Funding Information: We would like to thank Christopher Merrikh and the other members (past and present) of the Merrikh lab, as well as Neil Osheroff and Felipe Cort{\'e}s Ledesma for helpful discussions. The authors would also like to thank Sara Mangiameli for revising the manuscript and Peter Graumann for sharing strains. This work was supported by National Institutes of Health awards DP2GM110773 and R01GM128191-02 to H.M., Research Royalty Funds from the University of Washington to H.M., the 5T32-AI055396-13 Bacterial Pathogenesis Training Grant ( University of Washington ) award to K.S.L., and the 1F32 AI140557-01 Ruth L. Kirschstein National Research Postdoctoral award to K.S.L. We would like to dedicate this paper to the late James Champoux, who discovered Top1 and discussed this project with us on various occasions during our time at the University of Washington. Funding Information: We would like to thank Christopher Merrikh and the other members (past and present) of the Merrikh lab, as well as Neil Osheroff and Felipe Cort?s Ledesma for helpful discussions. The authors would also like to thank Sara Mangiameli for revising the manuscript and Peter Graumann for sharing strains. This work was supported by National Institutes of Health awards DP2GM110773 and R01GM128191-02 to H.M. Research Royalty Funds from the University of Washington to H.M. the 5T32-AI055396-13 Bacterial Pathogenesis Training Grant (University of Washington) award to K.S.L. and the 1F32 AI140557-01 Ruth L. Kirschstein National Research Postdoctoral award to K.S.L. We would like to dedicate this paper to the late James Champoux, who discovered Top1 and discussed this project with us on various occasions during our time at the University of Washington. K.S.L. and H.M. designed and performed the experiments, analyzed the data, and wrote the paper. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

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N2 - Conflicts between the replication and transcription machineries have profound effects on chromosome duplication, genome organization, and evolution across species. Head-on conflicts (lagging-strand genes) are significantly more detrimental than codirectional conflicts (leading-strand genes). The fundamental reason for this difference is unknown. Here, we report that topological stress significantly contributes to this difference. We find that head-on, but not codirectional, conflict resolution requires the relaxation of positive supercoils by the type II topoisomerases DNA gyrase and Topo IV, at least in the Gram-positive model bacterium Bacillus subtilis. Interestingly, our data suggest that after positive supercoil resolution, gyrase introduces excessive negative supercoils at head-on conflict regions, driving pervasive R-loop formation. Altogether, our results reveal a fundamental mechanistic difference between the two types of encounters, addressing a long-standing question in the field of replication-transcription conflicts.

AB - Conflicts between the replication and transcription machineries have profound effects on chromosome duplication, genome organization, and evolution across species. Head-on conflicts (lagging-strand genes) are significantly more detrimental than codirectional conflicts (leading-strand genes). The fundamental reason for this difference is unknown. Here, we report that topological stress significantly contributes to this difference. We find that head-on, but not codirectional, conflict resolution requires the relaxation of positive supercoils by the type II topoisomerases DNA gyrase and Topo IV, at least in the Gram-positive model bacterium Bacillus subtilis. Interestingly, our data suggest that after positive supercoil resolution, gyrase introduces excessive negative supercoils at head-on conflict regions, driving pervasive R-loop formation. Altogether, our results reveal a fundamental mechanistic difference between the two types of encounters, addressing a long-standing question in the field of replication-transcription conflicts.

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KW - Type II topoisomerases

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Topological stress is responsible for the detrimental outcomes of head-on replication-transcription conflicts

Abstract

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Keywords

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