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  • PMID: 27899603 was deleted because it is a duplicate of PMID: 28180284
Nucleic Acids Res. 2017 Feb 17;45(3):1130-1143. doi: 10.1093/nar/gkw1014.

Promiscuous DNA-binding of a mutant zinc finger protein corrupts the transcriptome and diminishes cell viability.

Author information

1
Cancer Genomics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
2
The Jackson Laboratory, Bar Harbor, ME, USA.
3
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA.
4
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
5
Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV, USA.
6
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.
7
School of Life and Environmental Sciences, The University of Sydney, NSW, Australia.
8
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia.
9
ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia.
10
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
11
Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.

Abstract

The rules of engagement between zinc finger transcription factors and DNA have been partly defined by in vitro DNA-binding and structural studies, but less is known about how these rules apply in vivo. Here, we demonstrate how a missense mutation in the second zinc finger of Krüppel-like factor-1 (KLF1) leads to degenerate DNA-binding specificity in vivo, resulting in ectopic transcription and anemia in the Nan mouse model. We employed ChIP-seq and 4sU-RNA-seq to identify aberrant DNA-binding events genome wide and ectopic transcriptional consequences of this binding. We confirmed novel sequence specificity of the mutant recombinant zinc finger domain by performing biophysical measurements of in vitro DNA-binding affinity. Together, these results shed new light on the mechanisms by which missense mutations in DNA-binding domains of transcription factors can lead to autosomal dominant diseases.

PMID:
28180284
PMCID:
PMC5388391
DOI:
10.1093/nar/gkw1014
[Indexed for MEDLINE]

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