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.
Highlights
Telomeres are the ends of linear chromosomes and in vertebrates are composed of DNA with the hexameric motif TTAGGG that are bound by a dedicated set of proteins
Their main functions are to prevent loss of genetic information due to replicative shortening and to prevent recognition of the ends of linear chromosomes from recognition as double-strand breaks. The latter is mediated by the six-protein shelterin complex that is constituently bound to telomeres and that contains the two DNA double-strand binders TRF1 and TRF2 and the single-strand binder POT1 [1]
In contrast to TRF1, TRF2 and HOT1, which do not recognize subtelomeric variant repeats [10,20], the in vitro binding pattern of ZBTB48 is rather reminiscent of NR2C/F transcription factors [4,21]
Summary
Telomeres are the ends of linear chromosomes and in vertebrates are composed of DNA with the hexameric motif TTAGGG that are bound by a dedicated set of proteins Their main functions are to prevent loss of genetic information due to replicative shortening and to prevent recognition of the ends of linear chromosomes from recognition as double-strand breaks. The latter is mediated by the six-protein shelterin complex that is constituently bound to telomeres and that contains the two DNA double-strand binders TRF1 and TRF2 and the single-strand binder POT1 [1]. NR2C/F transcription factors have been described to bind to subtelomeric variant repeats in ALT cells, to promote targeted telomere insertion (TTI) and more generally recombination events at telomeres in the interplay with the chromatin remodelling NuRD complex and the zinc finger protein ZNF827 [4,5]
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