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Author Notes:

Correspondence: todd.macfarlan@nih.gov; xcheng5@mdanderson.org.

These authors contributed equally to this work: A.P. and P.Y.

A.P. performed crystallographic and in vitro binding assays; P.Y. and M.T. performed reporter assays, ChIP-qPCR, Co-IP, and evolutionary analyses; with assistance from M.P. (cloning, purification and crystallization), Y.W. (rescue studies), D.H. and G.W. (luciferase assays), and J.R.H. (crystallography).

M-A.S. performed computational and evolutionary analysis.

T.S.M. initiated this collaborative work and together with X.Z. and X.C. organized and designed the scope of the study.

All authors were involved in analyzing data and preparing the manuscript.

We thank C.K-James Shen for providing human ZNF568 constructs and helpful discussion and B. Baker of New England Biolabs for synthesizing the oligonucleotides.

The authors declare no competing interests.


Research Funding:

The Department of Biochemistry of Emory University School of Medicine supported the use of SER-CAT beamlines.

This work was supported by grants from the National Institutes of Health GM049245-24 (X.Z. and X.C.), 1ZIAHD008933 (T.S.M), and CPRIT-RR160029 (X.C.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology

DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins

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Journal Title:

Analytical Cellular Pathology / Cellular Oncology


Volume 173, Number 1


, Pages 221-+

Type of Work:

Article | Post-print: After Peer Review


Tandem zinc finger (ZF) proteins are the largest and most rapidly diverging family of DNA-binding transcription regulators in mammals. ZFP568 represses a transcript of placental-specific insulin like growth factor 2 (Igf2-P0) in mice. ZFP568 binds a 24-base pair sequence-specific element upstream of Igf2-P0 via the eleven-ZF array. Both DNA and protein conformations deviate from the conventional one finger-three bases recognition, with individual ZFs contacting 2, 3, or 4 bases and recognizing thymine on the opposite strand. These interactions arise from a shortened minor groove caused by an AT-rich stretch, suggesting adaptability of ZF arrays to sequence variations. Despite conservation in mammals, mutations at Igf2 and ZFP568 reduce their binding affinity in chimpanzee and humans. Our studies provide important insights into the evolutionary and structural dynamics of ZF-DNA interactions that play a key role in mammalian development and evolution. Evolutionary and structure-function dynamics of zinc finger-DNA interactions reveal unconventional recognition codes and co-evolution of ZFP568 and its target gene Igf2 in mammals.

Copyright information:

© 2018 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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