SspABCD-SspE is a Phosphorothioation-sensing Bacterial Defence System with Broad Anti-phage Activities

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2020 Apr 7

PMID 32251370

Citations 58

Authors

Xiaolin Xiong

Geng Wu

Yue Wei

Liqiong Liu

Yubing Zhang

Rui Su

Xianyue Jiang

Mengxue Li

Haiyan Gao

Xihao Tian

Yizhou Zhang

Li Hu

Si Chen

You Tang

Susu Jiang

Ruolin Huang

Zhiqiang Li

Yunfu Wang

Zixin Deng

Jiawei Wang

Peter C Dedon

Shi Chen

Lianrong Wang

Affiliations

Soon will be listed here.

Abstract

Bacteria have evolved diverse mechanisms to fend off predation by bacteriophages. We previously identified the Dnd system, which uses DndABCDE to insert sulfur into the DNA backbone as a double-stranded phosphorothioate (PT) modification, and DndFGH, a restriction component. Here, we describe an unusual SspABCD-SspE PT system in Vibrio cyclitrophicus, Escherichia coli and Streptomyces yokosukanensis, which has distinct genetic organization, biochemical functions and phenotypic behaviour. SspABCD confers single-stranded and high-frequency PTs with SspB acting as a nickase and possibly introducing nicks to facilitate sulfur incorporation. Strikingly, SspABCD coupled with SspE provides protection against phages in unusual ways: (1) SspE senses sequence-specific PTs by virtue of its PT-stimulated NTPase activity to exert its anti-phage activity, and (2) SspE inhibits phage propagation by introducing nicking damage to impair phage DNA replication. These results not only expand our knowledge about the diversity and functions of DNA PT modification but also enhance our understanding of the known arsenal of defence systems.

Citing Articles

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Nucleic acid recognition during prokaryotic immunity.

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A DNA phosphorothioation pathway via adenylated intermediate modulates Tdp machinery.

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Molecular basis of the phosphorothioation-sensing antiphage defense system IscS-DndBCDE-DndI.

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References

Yamaguchi Y, Park J, Inouye M . Toxin-antitoxin systems in bacteria and archaea. Annu Rev Genet. 2011; 45:61-79. DOI: 10.1146/annurev-genet-110410-132412. View

Tock M, Dryden D . The biology of restriction and anti-restriction. Curr Opin Microbiol. 2005; 8(4):466-72. DOI: 10.1016/j.mib.2005.06.003. View

Dy R, Przybilski R, Semeijn K, Salmond G, Fineran P . A widespread bacteriophage abortive infection system functions through a Type IV toxin-antitoxin mechanism. Nucleic Acids Res. 2014; 42(7):4590-605. PMC: 3985639. DOI: 10.1093/nar/gkt1419. View

Marraffini L . CRISPR-Cas immunity in prokaryotes. Nature. 2015; 526(7571):55-61. DOI: 10.1038/nature15386. View

Swarts D, Jore M, Westra E, Zhu Y, Janssen J, Snijders A . DNA-guided DNA interference by a prokaryotic Argonaute. Nature. 2014; 507(7491):258-261. PMC: 4697943. DOI: 10.1038/nature12971. View

Goldfarb T, Sberro H, Weinstock E, Cohen O, Doron S, Charpak-Amikam Y . BREX is a novel phage resistance system widespread in microbial genomes. EMBO J. 2014; 34(2):169-83. PMC: 4337064. DOI: 10.15252/embj.201489455. View

Ofir G, Melamed S, Sberro H, Mukamel Z, Silverman S, Yaakov G . DISARM is a widespread bacterial defence system with broad anti-phage activities. Nat Microbiol. 2017; 3(1):90-98. PMC: 5739279. DOI: 10.1038/s41564-017-0051-0. View

Willbanks A, Leary M, Greenshields M, Tyminski C, Heerboth S, Lapinska K . The Evolution of Epigenetics: From Prokaryotes to Humans and Its Biological Consequences. Genet Epigenet. 2016; 8:25-36. PMC: 4973776. DOI: 10.4137/GEG.S31863. View

Blow M, Clark T, Daum C, Deutschbauer A, Fomenkov A, Fries R . The Epigenomic Landscape of Prokaryotes. PLoS Genet. 2016; 12(2):e1005854. PMC: 4752239. DOI: 10.1371/journal.pgen.1005854. View

10.

Wang L, Chen S, Xu T, Taghizadeh K, Wishnok J, Zhou X . Phosphorothioation of DNA in bacteria by dnd genes. Nat Chem Biol. 2007; 3(11):709-10. DOI: 10.1038/nchembio.2007.39. View

11.

Thiaville J, Kellner S, Yuan Y, Hutinet G, Thiaville P, Jumpathong W . Novel genomic island modifies DNA with 7-deazaguanine derivatives. Proc Natl Acad Sci U S A. 2016; 113(11):E1452-9. PMC: 4801273. DOI: 10.1073/pnas.1518570113. View

12.

Zhou X, He X, Liang J, Li A, Xu T, Kieser T . A novel DNA modification by sulphur. Mol Microbiol. 2005; 57(5):1428-38. DOI: 10.1111/j.1365-2958.2005.04764.x. View

13.

Eckstein F, Gish G . Phosphorothioates in molecular biology. Trends Biochem Sci. 1989; 14(3):97-100. DOI: 10.1016/0968-0004(89)90130-8. View

14.

Gan R, Wu X, He W, Liu Z, Wu S, Chen C . DNA phosphorothioate modifications influence the global transcriptional response and protect DNA from double-stranded breaks. Sci Rep. 2014; 4:6642. PMC: 4198939. DOI: 10.1038/srep06642. View

15.

Cao B, Cheng Q, Gu C, Yao F, Demott M, Zheng X . Pathological phenotypes and in vivo DNA cleavage by unrestrained activity of a phosphorothioate-based restriction system in Salmonella. Mol Microbiol. 2014; 93(4):776-85. PMC: 4414249. DOI: 10.1111/mmi.12692. View

16.

Xu T, Yao F, Zhou X, Deng Z, You D . A novel host-specific restriction system associated with DNA backbone S-modification in Salmonella. Nucleic Acids Res. 2010; 38(20):7133-41. PMC: 2978375. DOI: 10.1093/nar/gkq610. View

17.

Chen C, Wang L, Chen S, Wu X, Gu M, Chen X . Convergence of DNA methylation and phosphorothioation epigenetics in bacterial genomes. Proc Natl Acad Sci U S A. 2017; 114(17):4501-4506. PMC: 5410841. DOI: 10.1073/pnas.1702450114. View

18.

Cao B, Chen C, Demott M, Cheng Q, Clark T, Xiong X . Genomic mapping of phosphorothioates reveals partial modification of short consensus sequences. Nat Commun. 2014; 5:3951. PMC: 4322921. DOI: 10.1038/ncomms4951. View

19.

Kellner S, Demott M, Cheng C, Russell B, Cao B, You D . Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability. Nat Chem Biol. 2017; 13(8):888-894. PMC: 5577368. DOI: 10.1038/nchembio.2407. View

20.

Wang L, Chen S, Vergin K, Giovannoni S, Chan S, Demott M . DNA phosphorothioation is widespread and quantized in bacterial genomes. Proc Natl Acad Sci U S A. 2011; 108(7):2963-8. PMC: 3041111. DOI: 10.1073/pnas.1017261108. View