Promiscuous restriction is a cellular defense strategy that confers fitness advantage to bacteria

Vasu, K.I.; Nagamalleswari, Easa; Nagaraja, Valakunja

doi:10.1073/pnas.1119226109

Cited by 33 publications

(30 citation statements)

References 58 publications

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“…Relaxed specificity could be typical to evolutionary intermediates whereby the methylase diverges beyond the coverage of its cognate restriction enzyme. However, contrary to the current dogma of absolute specificity, broad specificity of the restriction enzyme may provide more efficient protection, as recently shown for phage defense by KpnI nuclease (41). The specificity of action of the restriction–methylation system has implications beyond foreign DNA.…”

Section: Discussionmentioning

confidence: 79%

Evolutionary transitions to new DNA methyltransferases through target site expansion and shrinkage

Rockah-Shmuel

Tawfik

2012

Nucleic Acids Research

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DNA-binding and modifying proteins show high specificity but also exhibit a certain level of promiscuity. Such latent promiscuous activities comprise the starting points for new protein functions, but this hypothesis presents a paradox: a new activity can only evolve if it already exists. How then, do novel activities evolve? DNA methyltransferases, for example, are highly divergent in their target sites, but how transitions toward novel sites occur remains unknown. We performed laboratory evolution of the DNA methyltransferase M.HaeIII. We found that new target sites emerged primarily through expansion of the original site, GGCC, and the subsequent shrinkage of evolved expanded sites. Variants evolved for sites that are promiscuously methylated by M.HaeIII [GG(A/T)CC and GGCGCC] carried mutations in ‘gate-keeper’ residues. They could thereby methylate novel target sites such as GCGC and GGATCC that were neither selected for nor present in M.HaeIII. These ‘generalist’ intermediates were further evolved to obtain variants with novel target specificities. Our results demonstrate the ease by which new DNA-binding and modifying specificities evolve and the mechanism by which they occur at both the protein and DNA levels.

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Section: Discussionmentioning

confidence: 79%

Evolutionary transitions to new DNA methyltransferases through target site expansion and shrinkage

Rockah-Shmuel

Tawfik

2012

Nucleic Acids Research

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“…NAPs have been shown to occlude and affect binding of TFs and other DNA binding proteins, such as restriction endonucleases and DNA methylation enzymes, suggesting a general role of NAPs in regulating genome accessibility by bending, wrapping and bridging the DNA structure [7], [12], [13], [27], [42], [76], [80], [81]. Additionally, NAPs influence DNA supercoiling, which has been shown to affect binding of the TFs Fis and OmpR in S. enterica [82], [83], providing another mechanism by which NAPs can change the chromosomal structure to influence TF-DNA binding.…”

Section: Discussionmentioning

confidence: 99%

Genome-scale Analysis of Escherichia coli FNR Reveals Complex Features of Transcription Factor Binding

et al. 2013

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FNR is a well-studied global regulator of anaerobiosis, which is widely conserved across bacteria. Despite the importance of FNR and anaerobiosis in microbial lifestyles, the factors that influence its function on a genome-wide scale are poorly understood. Here, we report a functional genomic analysis of FNR action. We find that FNR occupancy at many target sites is strongly influenced by nucleoid-associated proteins (NAPs) that restrict access to many FNR binding sites. At a genome-wide level, only a subset of predicted FNR binding sites were bound under anaerobic fermentative conditions and many appeared to be masked by the NAPs H-NS, IHF and Fis. Similar assays in cells lacking H-NS and its paralog StpA showed increased FNR occupancy at sites bound by H-NS in WT strains, indicating that large regions of the genome are not readily accessible for FNR binding. Genome accessibility may also explain our finding that genome-wide FNR occupancy did not correlate with the match to consensus at binding sites, suggesting that significant variation in ChIP signal was attributable to cross-linking or immunoprecipitation efficiency rather than differences in binding affinities for FNR sites. Correlation of FNR ChIP-seq peaks with transcriptomic data showed that less than half of the FNR-regulated operons could be attributed to direct FNR binding. Conversely, FNR bound some promoters without regulating expression presumably requiring changes in activity of condition-specific transcription factors. Such combinatorial regulation may allow Escherichia coli to respond rapidly to environmental changes and confer an ecological advantage in the anaerobic but nutrient-fluctuating environment of the mammalian gut.

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“…The catalytic promiscuity exhibited by the enzyme under in vivo conditions suggests a functional role. Studies carried out with R.KpnI revealed that retaining broad specificity in DNA cleavage characteristics provided a selective advantage to the host by better targeting foreign invading genetic elements (145). It is possible that a relaxed specificity of REases might also serve a hithertounknown function(s) in the organism.…”

Section: Promiscuity In Cofactor Utilization and Substrate Specificitymentioning

confidence: 99%

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

Vasu

Nagaraja

2013

Microbiol Mol Biol Rev

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521

462

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SUMMARY Restriction-modification (R-M) systems are ubiquitous and are often considered primitive immune systems in bacteria. Their diversity and prevalence across the prokaryotic kingdom are an indication of their success as a defense mechanism against invading genomes. However, their cellular defense function does not adequately explain the basis for their immaculate specificity in sequence recognition and nonuniform distribution, ranging from none to too many, in diverse species. The present review deals with new developments which provide insights into the roles of these enzymes in other aspects of cellular function. In this review, emphasis is placed on novel hypotheses and various findings that have not yet been dealt with in a critical review. Emerging studies indicate their role in various cellular processes other than host defense, virulence, and even controlling the rate of evolution of the organism. We also discuss how R-M systems could have successfully evolved and be involved in additional cellular portfolios, thereby increasing the relative fitness of their hosts in the population.

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Promiscuous restriction is a cellular defense strategy that confers fitness advantage to bacteria

Cited by 33 publications

References 58 publications

Evolutionary transitions to new DNA methyltransferases through target site expansion and shrinkage

Evolutionary transitions to new DNA methyltransferases through target site expansion and shrinkage

Genome-scale Analysis of Escherichia coli FNR Reveals Complex Features of Transcription Factor Binding

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

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