New Insights into DNA Recognition by Zinc Fingers Revealed by Structural Analysis of the Oncoprotein ZNF217

Vandevenne, Marylène; Jacques, D.A.; Artuz, C.D.; Nguyen, Charlene; Kwan, Ann H.; Segal, David J.; Matthews, Jacqueline M.; Crossley, Merlin; Guss, J. Mitchell; Mackay, Joel P.

doi:10.1074/jbc.m112.441451

Cited by 39 publications

(43 citation statements)

References 75 publications

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“…If these distinct binding events induce shift changes that are relatively uncorrelated, the overall observed changes will be small. Consistent with this idea, we recently observed substantially smaller chemical shift changes when the ZF protein ZNF217 bound to a non-specific DNA target than when it bound a sequence for which it had specificity (50). This explanation would also partially account for our mutagenesis data, which indicate that the contribution of individual residues to overall affinity is small, perhaps due to the existence of a number of binding modes.…”

Section: Discussionmentioning

confidence: 56%

The zinc fingers of YY1 bind single-stranded RNA with low sequence specificity

et al. 2016

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Classical zinc fingers (ZFs) are traditionally considered to act as sequence-specific DNA-binding domains. More recently, classical ZFs have been recognised as potential RNA-binding modules, raising the intriguing possibility that classical-ZF transcription factors are involved in post-transcriptional gene regulation via direct RNA binding. To date, however, only one classical ZF-RNA complex, that involving TFIIIA, has been structurally characterised. Yin Yang-1 (YY1) is a multi-functional transcription factor involved in many regulatory processes, and binds DNA via four classical ZFs. Recent evidence suggests that YY1 also interacts with RNA, but the molecular nature of the interaction remains unknown. In the present work, we directly assess the ability of YY1 to bind RNA using in vitro assays. Systematic Evolution of Ligands by EXponential enrichment (SELEX) was used to identify preferred RNA sequences bound by the YY1 ZFs from a randomised library over multiple rounds of selection. However, a strong motif was not consistently recovered, suggesting that the RNA sequence selectivity of these domains is modest. YY1 ZF residues involved in binding to single-stranded RNA were identified by NMR spectroscopy and found to be largely distinct from the set of residues involved in DNA binding, suggesting that interactions between YY1 and ssRNA constitute a separate mode of nucleic acid binding. Our data are consistent with recent reports that YY1 can bind to RNA in a low-specificity, yet physiologically relevant manner.

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Section: Discussionmentioning

confidence: 56%

The zinc fingers of YY1 bind single-stranded RNA with low sequence specificity

et al. 2016

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“…(De et al, 2014-this issue) show that, although the chemical shift changes observed for ETV6-ETS are overall in the same direction for both specific and non-specific complexes, the magnitude of the changes is significantly smaller for the latter complex. We noted a similar pattern in our analysis of the DNA-binding properties of the zinc-finger protein ZNF217 [10] and the spectra shown in the study of the HoxD9 homeodomain [18] appear to tell a similar story. In each case, the authors report that the protein is N 90% saturated with DNA, which means that the smaller chemical shift changes do not arise from incomplete complex formation.…”

supporting

confidence: 59%

“…However, a picture is beginning to emerge that the overall geometry of DNA recognition is conserved between cognate and non-cognate interactions. An NMR structure of the lac repressor (LacI) DBD (DNA-binding domain) bound to nonspecific DNA [9] and NMR studies of both homeodomain [7] and zinc-finger domains [10,11] show that the canonical DNA-binding surface is used in nonspecific interactions.…”

mentioning

confidence: 99%

Transcription Factor Seeks DNA—Cognate Site Preferred

Mackay

2014

Journal of Molecular Biology

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“…S5). Comparable patterns of relative NMR spectral changes have been reported for the HMG-box 26 and ZNF217 zinc finger 27 proteins bound to non-specific versus specific DNA oligonucleotides. This is not a trivial result of incomplete saturation of the ETV6 D446 –DNA nonsp complex, as the protein was ~ 98 % bound (Supplemental Fig.…”

Section: Etv6 Binds Non-specific Dna Via the Canonical Ets Domain Intmentioning

confidence: 86%

Steric Mechanism of Auto-Inhibitory Regulation of Specific and Non-Specific DNA Binding by the ETS Transcriptional Repressor ETV6

Chan

Coyne

et al. 2014

Journal of Molecular Biology

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DNA binding by the ETS transcriptional repressor ETV6 (or TEL) is auto-inhibited ~ 50-fold due to an α-helix that sterically blocks its ETS domain binding interface. Using NMR spectroscopy, we demonstrate that this marginally-stable helix is unfolded, and not displaced to a non-inhibitory position, when ETV6 is bound to DNA containing a consensus 5’GGAA3’ recognition site. Although significantly lower in affinity, binding to non-specific DNA is auto-inhibited ~ 5-fold and also accompanied by helix unfolding. Based on NMR chemical shift perturbations, both specific and non-specific DNA are bound via the same canonical ETS domain interface. However, spectral perturbations are smaller for the non-specific complex, suggesting weaker and less well-defined interactions than in the specific complex. In parallel, the crystal structure of ETV6 bound to a specific DNA duplex was determined. The structure of this complex reveals that a non-conserved histidine residue in the ETS domain recognition helix helps establish the specificity of ETV6 for DNA-binding sites containing 5’GGAA3’ versus 5’GGAT3’. These studies provide a unified steric mechanism for attenuating ETV6 binding to both specific and non-specific DNA and expand the repertoire of characterized auto-inhibitory strategies utilized to regulate ETS factors.

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New Insights into DNA Recognition by Zinc Fingers Revealed by Structural Analysis of the Oncoprotein ZNF217

Cited by 39 publications

References 75 publications

The zinc fingers of YY1 bind single-stranded RNA with low sequence specificity

The zinc fingers of YY1 bind single-stranded RNA with low sequence specificity

Transcription Factor Seeks DNA—Cognate Site Preferred

Steric Mechanism of Auto-Inhibitory Regulation of Specific and Non-Specific DNA Binding by the ETS Transcriptional Repressor ETV6

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