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ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator. (EMBO Rep, May 2017)

Jahn A1,2, Rane G3, Paszkowski-Rogacz M1, Sayols S4, Bluhm A4, Han CT4, Draškovič I5, Londoño-Vallejo JA5, Kumar AP3,6,7, Buchholz F8,9,10,11,12, Butter F13, Kappei D14.

Author information
1 Medical Systems Biology, UCC, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
2 Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
3 Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.
4 Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany.
5 Telomeres & Cancer Laboratory, UMR3244, Institut Curie-CNRS-UPMC, Paris Cedex 05, France.
6 Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore City, Singapore.
7 Curtin Medical School, Faculty of Health Sciences Curtin University, Perth, Australia.
8 Medical Systems Biology, UCC, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany
9 Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
10 German Cancer Research Center (DKFZ), Heidelberg, Germany.
11 German Cancer Consortium (DKTK) Partner Site Dresden, Dresden, Germany.
12 National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
13 Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany
14 Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore

Abstract
Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1/HMBOX1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48/HKR3/TZAP has been described as a novel telomere-associated factor in the vertebrate lineage. Here, we show that ZBTB48 binds directly both to telomeric and to subtelomeric variant repeat sequences. ZBTB48 is found at telomeres of human cancer cells regardless of the mode of telomere maintenance and it acts as a negative regulator of telomere length. In addition to its telomeric function, we demonstrate through a combination of RNAseq, ChIPseq and expression proteomics experiments that ZBTB48 acts as a transcriptional activator on a small set of target genes, including mitochondrial fission process 1 (MTFP1). This discovery places ZBTB48 at the interface of telomere length regulation, transcriptional control and mitochondrial metabolism.

KEYWORDS: gene regulation; mitochondria; telomere length; telomeres; transcription factor

PMID: 28500257