8388–8398 Nucleic Acids Research, 2019, Vol. 47, No. 16 Published online 21 June 2019 doi: 10.1093/nar/gkz557 Structural basis of specific DNA binding by the transcription factor ZBTB24 Ren Ren1,†, Swanand Hardikar1,†, John R. Horton1, Yue Lu1, Yang Zeng1,2,AnupK.Singh1, Kevin Lin1, Luis Della Coletta1, Jianjun Shen1,2, Celine Shuet Lin Kong3, Hideharu Hashimoto4, Xing Zhang1, Taiping Chen1,2,* and Xiaodong Cheng 1,2,*
1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 2
Houston, TX 77030, USA, Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Downloaded from https://academic.oup.com/nar/article/47/16/8388/5521786 by guest on 23 September 2021 Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA, 3Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA and 4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
Received October 13, 2018; Revised June 07, 2019; Editorial Decision June 11, 2019; Accepted June 13, 2019
ABSTRACT INTRODUCTION ZBTB24, encoding a protein of the ZBTB family ZBTB (zinc-finger- and BTB domain-containing) proteins, of transcriptional regulators, is one of four known characterized by the presence of an N-terminal BTB genes––the other three being DNMT3B, CDCA7 and (broad-complex, tram-track, and bric-a-brac)` domain [also HELLS––that are mutated in immunodeficiency, cen- known as POZ (poxvirus and zinc finger) domain] and a tromeric instability and facial anomalies (ICF) syn- C-terminal domain with tandem C2H2 Kr¨uppel-type zinc fingers (ZFs), are a large family of evolutionarily con- drome, a genetic disorder characterized by DNA hy- served transcriptional regulators (1). The BTB domain pomethylation and antibody deficiency. The molec- mediates homomeric or heteromeric dimerization and in- ular mechanisms by which ZBTB24 regulates gene teracts with histone deacetylase (HDAC)-containing core- expression and the biological functions of ZBTB24 pressor complexes, such as the NCOR (nuclear recep- are poorly understood. Here, we identified a 12-bp tor corepressor), SMRT (silencing mediator of retinoic consensus sequence [CT(G/T)CCAGGACCT] occu- acid and thyroid hormone receptor), BCOR (BCL6 core- pied by ZBTB24 in the mouse genome. The sequence pressor) and SIN3A/3B complexes (2). The ZF domain is present at multiple loci, including the Cdca7 pro- mediates sequence-specific DNA binding and, in some moter region, and ZBTB24 binding is mostly as- cases, also mediates protein–protein interactions. For exam- ple, ZBTB16/PLZF (promyelocytic leukemia zinc finger) sociated with gene activation. Crystallography and / DNA-binding data revealed that the last four of the and ZBTB17 MIZ-1 (Myc-interacting zinc finger protein- 1) reportedly interact with p300 and MYC, respectively, eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 con- via their ZF domains (3,4). Generally considered tran- fer specificity of DNA binding. Two ICF missense scriptional repressors, ZBTB proteins have been impli- mutations have been identified in the ZBTB24 ZF cated in a variety of developmental and cellular pro- domain, which alter zinc-binding cysteine residues. cesses. Of particular note, several ZBTB proteins, includ- We demonstrated that the corresponding C382Y and ing ZBTB7A/LRF (lymphoma/leukemia-related factor), C407G mutations in mouse ZBTB24 abolish specific ZBTB16/PLZF, ZBTB27/BCL6 (B-cell lymphoma 6) and DNA binding and fail to induce Cdca7 expression. ZBTB32/PLZP (PLZF-like zinc finger protein), play regu- Our analyses indicate and suggest a structural basis latory roles in lymphoid development, function and malig- for the sequence specific recognition by a transcrip- nancies (5–7). tion factor centrally important for the pathogenesis ZBTB24 is one of several genes that are mutated in im- of ICF syndrome. munodeficiency, centromeric instability and facial anoma- lies (ICF) syndrome, a rare autosomal recessive disorder (8,9). Cases carrying ZBTB24 mutations are known as ICF type 2 or ICF2 (10). The other genes associated with
*To whom correspondence should be addressed. Tel: +1 713 834 6274; Email: [email protected] Correspondence may also be addressed to Taiping Chen. Tel: +1 512 237 9479; Email: [email protected] †The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.