TY - JOUR
T1 - Structural basis for transcription factor ZBTB7A recognition of DNA and effects of ZBTB7A somatic mutations that occur in human acute myeloid leukemia
AU - Ren, Ren
AU - Horton, John R.
AU - Chen, Qin
AU - Yang, Jie
AU - Liu, Bin
AU - Huang, Yun
AU - Blumenthal, Robert M.
AU - Zhang, Xing
AU - Cheng, Xiaodong
N1 - Funding Information:
We thank Prof Merlin Crossley of University of New South Wales for providing the initial ZBTB7A construct; Ms Yu Cao of MD Anderson Cancer Center (MDACC) for technical assistance throughout the study; Dr Collene R. Jeter of MDACC for help with confocal microscopy and Dr Margarida A. Santos of MDACC for comments on the article. We thank the beamline scientists of the Southeast Regional Collaborative Access Team at the Advanced Photon Source, Argonne National Laboratory, USA. The use of the Southeast Regional Collaborative Access Team is supported by its member institutions and equipment grants from the US National Institutes of Health (grant nos.: S10_RR25528 , S10_RR028976 , and S10_OD027000 ). Use of the Advanced Photon Source was supported by the US Department of Energy , Office of Science , Office of Basic Energy Sciences , under contract W-31-109-Eng-38 . The work was supported by the US National Institutes of Health (grant no.: R35GM134744 ) and the Cancer Prevention and Research Institute of Texas (grant no.: RR160029 ). The use of the Flow Cytometry and Cell Imaging Core facility is supported by CPRIT grant RP170628 .
Funding Information:
We thank Prof Merlin Crossley of University of New South Wales for providing the initial ZBTB7A construct; Ms Yu Cao of MD Anderson Cancer Center (MDACC) for technical assistance throughout the study; Dr Collene R. Jeter of MDACC for help with confocal microscopy and Dr Margarida A. Santos of MDACC for comments on the article. We thank the beamline scientists of the Southeast Regional Collaborative Access Team at the Advanced Photon Source, Argonne National Laboratory, USA. The use of the Southeast Regional Collaborative Access Team is supported by its member institutions and equipment grants from the US National Institutes of Health (grant nos.: S10_RR25528, S10_RR028976, and S10_OD027000). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. The work was supported by the US National Institutes of Health (grant no.: R35GM134744) and the Cancer Prevention and Research Institute of Texas (grant no.: RR160029). The use of the Flow Cytometry and Cell Imaging Core facility is supported by CPRIT grant RP170628. X. Z. and X. C. conceptualization; X. C. methodology; B. L. Y. H. and R. M. B. formal analysis; R. R. J. R. H. and Q. C. investigation; X. C. writing–original draft; R. M. B. writing–review & editing; J. Y. validation; X. Z. supervision; X. Z. project administration; X. C. funding acquisition. X. C. is a CPRIT Scholar in Cancer Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2023 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - AML t(8;21)
KW - C2H2 zinc-finger transcription factors
KW - cancer metabolism
KW - ZBTB7A
KW - ZBTB7A somatic mutations
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U2 - 10.1016/j.jbc.2023.102885
DO - 10.1016/j.jbc.2023.102885
M3 - Article
C2 - 36626981
AN - SCOPUS:85148479735
SN - 0021-9258
VL - 299
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
M1 - 102885
ER -