DNA Mimic Proteins: Functions, Structures, and Bioinformatic Analysis

Wang, Hao Ching; Ho, Chun Han; Hsu, Kai Cheng; Yang, Jinn-Moon; Wang, Andrew H.J.

doi:10.1021/bi5002689

Cited by 48 publications

(59 citation statements)

References 66 publications

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“…Indeed, phage have evolved a wide variety of strategies to repurpose host cell functions for their own benefit, including inhibition of key bacterial proteins. These include many examples of proteins that target DNA replication, recombination and repair factors, which often share the primary structure characteristics of DNA mimic proteins (Wang et al, 2014). Characterisation of DNA mimic proteins provides an attractive route towards the identification and validation of novel antibiotic targets, because bacterial DNA transactions are not only crucial for survival but are structurally orthogonal to their eukaryotic counterparts (Robinson et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones

Wilkinson

Troman

Ismah

et al. 2016

eLife

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Our previous paper (Wilkinson et al, 2016) used high-resolution cryo-electron microscopy to solve the structure of the Escherichia coli RecBCD complex, which acts in both the repair of double-stranded DNA breaks and the degradation of bacteriophage DNA. To counteract the latter activity, bacteriophage λ encodes a small protein inhibitor called Gam that binds to RecBCD and inactivates the complex. Here, we show that Gam inhibits RecBCD by competing at the DNA-binding site. The interaction surface is extensive and involves molecular mimicry of the DNA substrate. We also show that expression of Gam in E. coli or Klebsiella pneumoniae increases sensitivity to fluoroquinolones; antibacterials that kill cells by inhibiting topoisomerases and inducing double-stranded DNA breaks. Furthermore, fluoroquinolone-resistance in K. pneumoniae clinical isolates is reversed by expression of Gam. Together, our data explain the synthetic lethality observed between topoisomerase-induced DNA breaks and the RecBCD gene products, suggesting a new co-antibacterial strategy.DOI: http://dx.doi.org/10.7554/eLife.22963.001

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Section: Discussionmentioning

confidence: 99%

Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones

Wilkinson

Troman

Ismah

et al. 2016

eLife

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“…Another possibility is that QseM has evolved as a DNA mimic (50) and is able to interfere with FseA and TraR through interaction with their DNAbinding regions. Alternatively, QseM may have evolved distinct sites with which it binds FseA and TraR, in which case a single QseM molecule may be able to inhibit FseA and TraR simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Ribosomal frameshifting and dual-target antiactivation restrict quorum-sensing–activated transfer of a mobile genetic element

Ramsay

Tester²,

Major³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Symbiosis islands are integrative and conjugative mobile genetic elements that convert nonsymbiotic rhizobia into nitrogen-fixing symbionts of leguminous plants. Excision of the Mesorhizobium loti symbiosis island ICEMlSym R7A is indirectly activated by quorum sensing through TraR-dependent activation of the excisionase gene rdfS. Here we show that a +1 programmed ribosomal frameshift (PRF) fuses the coding sequences of two TraR-activated genes, msi172 and msi171, producing an activator of rdfS expression named Frameshifted excision activator (FseA). Mass-spectrometry and mutational analyses indicated that the PRF occurred through +1 slippage of the tRNA phe from UUU to UUC within a conserved msi172-encoded motif. FseA activated rdfS expression in the absence of ICEMlSym R7A , suggesting that it directly activated rdfS transcription, despite being unrelated to any characterized DNA-binding proteins. Bacterial two-hybrid and gene-reporter assays demonstrated that FseA was also bound and inhibited by the ICEMlSym R7A -encoded quorum-sensing antiactivator QseM. Thus, activation of ICEMlSym R7A excision is counteracted by TraR antiactivation, ribosomal frameshifting, and FseA antiactivation. This robust suppression likely dampens the inherent biological noise present in the quorum-sensing autoinduction circuit and ensures that ICEMlSym R7A transfer only occurs in a subpopulation of cells in which both qseM expression is repressed and FseA is translated. The architecture of the ICEMlSym R7A transfer regulatory system provides an example of how a set of modular components have assembled through evolution to form a robust genetic toggle that regulates gene transcription and translation at both single-cell and cell-population levels.quorum sensing | antiactivator | ribosomal frameshift | ICE | horizontal gene transfer

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“…In this case, the Ant commonly mimics the structure of DNA to bind competitively to the Rep (5). DNA mimic proteins have been discovered in prokaryotes, eukaryotes, and viruses (5,6); these proteins are involved in various DNA regulatory functions, including transcriptional control (7) and DNA packaging (8). Although the structures of DNA-mimic proteins are diverse, they have similar surface-charge distributions that mimic the surface properties of DNA (5).…”

mentioning

confidence: 99%

“…DNA mimic proteins have been discovered in prokaryotes, eukaryotes, and viruses (5,6); these proteins are involved in various DNA regulatory functions, including transcriptional control (7) and DNA packaging (8). Although the structures of DNA-mimic proteins are diverse, they have similar surface-charge distributions that mimic the surface properties of DNA (5). Despite the previous structural and functional studies of Ant, the only known mechanism by which most Ants disable a Rep is through a simple competitivebinding mechanism.…”

mentioning

confidence: 99%

Noncanonical DNA-binding mode of repressor and its disassembly by antirepressor

Kim

Son

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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DNA-binding repressors are involved in transcriptional repression in many organisms. Disabling a repressor is a crucial step in activating expression of desired genes. Thus, several mechanisms have been identified for the removal of a stably bound repressor (Rep) from the operator. Here, we describe an uncharacterized mechanism of noncanonical DNA binding and induction by a Rep from the temperate Salmonella phage SPC32H; this mechanism was revealed using the crystal structures of homotetrameric Rep (92–198) and a hetero-octameric complex between the Rep and its antirepressor (Ant). The canonical method of inactivating a repressor is through the competitive binding of the antirepressor to the operator-binding site of the repressor; however, these studies revealed several noncanonical features. First, Ant does not compete for the DNA-binding region of Rep. Instead, the tetrameric Ant binds to the C-terminal domains of two asymmetric Rep dimers. Simultaneously, Ant facilitates the binding of the Rep N-terminal domains to Ant, resulting in the release of two Rep dimers from the bound DNA. Second, the dimer pairs of the N-terminal DNA-binding domains originate from different dimers of a Rep tetramer (trans model). This situation is different from that of other canonical Reps, in which two N-terminal DNA-binding domains from the same dimeric unit form a dimer upon DNA binding (cis model). On the basis of these observations, we propose a noncanonical model for the reversible inactivation of a Rep by an Ant.

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DNA Mimic Proteins: Functions, Structures, and Bioinformatic Analysis

Cited by 48 publications

References 66 publications

Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones

Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones

Ribosomal frameshifting and dual-target antiactivation restrict quorum-sensing–activated transfer of a mobile genetic element

Noncanonical DNA-binding mode of repressor and its disassembly by antirepressor

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