title: Bacterial Autoimmunity Due to a Restriction-Modification System.
abstract: Restriction-modification (RM) systems represent a minimal and ubiquitous biological system of self/non-self discrimination in prokaryotes [1], which protects hosts from exogenous DNA [2]. The mechanism is based on the balance between methyltransferase (M) and cognate restriction endonuclease (R). M tags endogenous DNA as self by methylating short specific DNA sequences called restriction sites, whereas R recognizes unmethylated restriction sites as non-self and introduces a double-stranded DNA break [3]. Restriction sites are significantly underrepresented in prokaryotic genomes [4-7], suggesting that the discrimination mechanism is imperfect and occasionally leads to autoimmunity due to self-DNA cleavage (self-restriction) [8]. Furthermore, RM systems can promote DNA recombination [9] and contribute to genetic variation in microbial populations, thus facilitating adaptive evolution [10]. However, cleavage of self-DNA by RM systems as elements shaping prokaryotic genomes has not been directly detected, and its cause, frequency, and outcome are unknown. We quantify self-restriction caused by two RM systems of Escherichia coli and find that, in agreement with levels of restriction site avoidance, EcoRI, but not EcoRV, cleaves self-DNA at a measurable rate. Self-restriction is a stochastic process, which temporarily induces the SOS response, and is followed by DNA repair, maintaining cell viability. We find that RM systems with higher restriction efficiency against bacteriophage infections exhibit a higher rate of self-restriction, and that this rate can be further increased by stochastic imbalance between R and M. Our results identify molecular noise in RM systems as a factor shaping prokaryotic genomes.
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria.
authors.forename: Maroš
authors.initials: M
authors.lastname: Pleška
authors.affiliation: Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Basic Science, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba Meguro-ku, 153-8902 Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Okura
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bergmiller
authors.affiliation: Department of Basic Science, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba Meguro-ku, 153-8902 Tokyo, Japan; Research Center for Complex Systems Biology, University of Tokyo, 3-8-1 Komaba Meguro-ku, 153-8902 Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Wakamoto
authors.affiliation: Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, USA; Department of Physics, New York University, 4 Washington Place, New York, NY 10003, USA.
authors.forename: Edo
authors.initials: E
authors.lastname: Kussell
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria. Electronic address: calin@ist.ac.at.
authors.forename: Călin C
authors.initials: CC
authors.lastname: Guet
mesh_terms: D015551:Autoimmunity; D001435:Bacteriophages / Q000502:physiology; D004260:DNA Repair; D015280:DNA Restriction-Modification Enzymes; D004926:Escherichia coli / Q000235:genetics* / Q000276:immunology* / Q000821:virology
chemical_list: D015280:DNA Restriction-Modification Enzymes