Structural Basis for Transcription Factor ZBTB7A Recognition of DNA and Effects of ZBTB7A Somatic Mutations That Occur in Human Acute Myeloid Leukemia

Authors

Ren Ren
John R Horton
Qin Chen
Jie Yang
Bin Liu
Yun Huang
Robert M Blumenthal
Xing Zhang
Xiaodong Cheng

Publication Date

2-1-2023

Journal

Journal of Biological Chemistry

Abstract

ZBTB7A belongs to a small family of transcription factors having three members in humans (7A, 7B, and 7C). They share a BTB/POZ protein interaction domain at the amino end and a zinc-finger DNA-binding domain at the carboxyl end. They control the transcription of a wide range of genes, having varied functions in hematopoiesis, oncogenesis, and metabolism (in particular glycolysis). ZBTB7A-binding profiles at gene promoters contain a consensus G(a/c)CCC motif, followed by a CCCC sequence in some instances. Structural and mutational investigations suggest that DNA-specific contacts with the four-finger tandem array of ZBTB7A are formed sequentially, initiated from ZF1-ZF2 binding to G(a/c)CCC before spreading to ZF3-ZF4, which bind the DNA backbone and the 3' CCCC sequence, respectively. Here, we studied some mutations found in t(8;21)-positive acute myeloid leukemia patients that occur within the ZBTB7A DNA-binding domain. We determined that these mutations generally impair ZBTB7A DNA binding, with the most severe disruptions resulting from mutations in ZF1 and ZF2, and the least from a frameshift mutation in ZF3 that results in partial mislocalization. Information provided here on ZBTB7A-DNA interactions is likely applicable to ZBTB7B/C, which have overlapping functions with ZBTB7A in controlling primary metabolism.

Keywords

Humans, Cell Line, Tumor, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Mutation, Transcription Factors, Zinc Fingers, Protein Domains, Protein Binding

Comments

Supplementary Materials

PMID: 36626981