DNA selection by the master transcription factor PU.1

J. Ross Terrell; Samuel J. Taylor; Amelia L. Schneider; Yue Lu; Tyler N. Vernon; Suela Xhani; Ryan H. Gumpper; Ming Luo; W. David Wilson; Ulrich Steidl; Gregory M.K. Poon

Cell Reports (Jul 2023)

DNA selection by the master transcription factor PU.1

J. Ross Terrell,
Samuel J. Taylor,
Amelia L. Schneider,
Yue Lu,
Tyler N. Vernon,
Suela Xhani,
Ryan H. Gumpper,
Ming Luo,
W. David Wilson,
Ulrich Steidl,
Gregory M.K. Poon

Affiliations

J. Ross Terrell: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Samuel J. Taylor: Departments of Cell Biology, Oncology, and Medicine, Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Blood Cancer Institute, and the Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Amelia L. Schneider: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Yue Lu: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Tyler N. Vernon: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Suela Xhani: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Ryan H. Gumpper: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Ming Luo: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
W. David Wilson: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Ulrich Steidl: Departments of Cell Biology, Oncology, and Medicine, Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Blood Cancer Institute, and the Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Corresponding author
Gregory M.K. Poon: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 7
p. 112671

Abstract

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Summary: The master transcriptional regulator PU.1/Spi-1 engages DNA sites with affinities spanning multiple orders of magnitude. To elucidate this remarkable plasticity, we have characterized 22 high-resolution co-crystallographic PU.1/DNA complexes across the addressable affinity range in myeloid gene transactivation. Over a purine-rich core (such as 5ʹ-GGAA-3ʹ) flanked by variable sequences, affinity is negotiated by direct readout on the 5ʹ flank via a critical glutamine (Q226) sidechain and by indirect readout on the 3ʹ flank by sequence-dependent helical flexibility. Direct readout by Q226 dynamically specifies PU.1’s characteristic preference for purines and explains the pathogenic mutation Q226E in Waldenström macroglobulinemia. The structures also reveal how disruption of Q226 mediates strand-specific inhibition by DNA methylation and the recognition of non-canonical sites, including the authentic binding sequence at the CD11b promoter. A re-synthesis of phylogenetic and structural data on the ETS family, considering the centrality of Q226 in PU.1, unifies the model of DNA selection by ETS proteins.

CP: Molecular biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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