DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins

• Type of Material: Article
• Authors: Anamika Patel, Emory University; Peng Yang, Eunice Kennedy Shriver National Institute of Child Health; Matthew Tinkham, Eunice Kennedy Shriver National Institute of Child Health; Mihika Pradhan, Emory University; Ming-An Sun, Eunice Kennedy Shriver National Institute of Child Health; Yixuan Wang, Eunice Kennedy Shriver National Institute of Child Health; Don Hoang, Eunice Kennedy Shriver National Institute of Child Health; Gernot Wolf, Eunice Kennedy Shriver National Institute of Child Health; John Horton, Emory University; Xing Zhang, University of Texas MD Anderson Cancer Center; Todd Macfarlan, Eunice Kennedy Shriver National Institute of Child Health; Xiaodong Cheng, Emory University
• Language: English
• Date: 2018-03-22
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2018.02.058
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 173
• Issue: 1
• Start Page: 221
• End Page: +
• Grant/Funding Information: 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.).; The Department of Biochemistry of Emory University School of Medicine supported the use of SER-CAT beamlines.
• Keywords: EMBRYONIC STEM-CELLS; Cell Biology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; SEQUENCE; METHYLATION; RECOGNITION; STRUCTURAL BASIS; GENES; HISTONE H3; SYSTEM; DOMAIN; METHYLTRANSFERASE; Science & Technology
• Research Categories: Chemistry, Biochemistry; Biology, Cell; Biology, Molecular

Abstract

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.