Abstract
Telomeres are nucleoprotein complexes at the ends of chromosomes and are indispensable for the protection and lengthening of terminal DNA. Despite the evolutionarily conserved roles of telomeres, the telomeric double-strand DNA (dsDNA)-binding proteins have evolved rapidly. Here, we identified double-strand telomeric DNA-binding proteins (DTN-1 and DTN-2) in Caenorhabditis elegans as non-canonical telomeric dsDNA-binding proteins. DTN-1 and DTN-2 are paralogous proteins that have three putative MYB-like DNA-binding domains and bind to telomeric dsDNA in a sequence-specific manner. DTN-1 and DTN-2 form complexes with the single-strand telomeric DNA-binding proteins POT-1 and POT-2 and constitutively localize to telomeres. The dtn-1 and dtn-2 genes function redundantly, and their simultaneous deletion results in progressive germline mortality, which accompanies telomere hyper-elongation and chromosomal bridges. Our study suggests that DTN-1 and DTN-2 are core shelterin components in C. elegans telomeres that act as negative regulators of telomere length and are essential for germline immortality.
Highlights
Telomeres at the ends of linear eukaryotic chromosomes are composed of tandem repeats of short G-rich DNA sequences – (TTAGGG)n in vertebrates – and sequence-specific DNA-binding proteins (Palm and de Lange, 2008)
Our findings suggest that DTN-1 and DTN-2 are bona fide telomeric double-strand DNA (dsDNA)-binding proteins in C. elegans and that they are indispensable for the maintenance of germline immortality and telomere length homeostasis
In order to identify novel telomeric proteins in C. elegans, we used a yeast two-hybrid (Y2H) approach to screen for protection of telomere (POT)-1-binding proteins from the C. elegans mixed-stage cDNA library, and we identified two functionally uncharacterized proteins encoded by the R06A4.2 and T12E12.3 genes (Figure 1A and Figure 1—figure supplement 1)
Summary
Telomeres at the ends of linear eukaryotic chromosomes are composed of tandem repeats of short G-rich DNA sequences – (TTAGGG)n in vertebrates – and sequence-specific DNA-binding proteins (Palm and de Lange, 2008). A deviation is found in budding yeast, where telomeric dsDNA is bound by the Rap protein with two tandem MYB domains (Konig et al, 1996; Krauskopf and Blackburn, 1996), and this deviation has been attributed to the atypical telomeric dsDNA sequence (heterogeneous and not GC-rich) in this organism (Cervenak et al, 2017) Another deviation is found in Caenorhabditis elegans, which. There have been several reports showing that some transcription factors and chromatin remodelers, such as CEH-37 and HMG-5, bind to telomeric dsDNA in C. elegans, but deletions of these factors did not show any chromosomal defects, leaving the true regulator of telomeric dsDNA unidentified (Im and Lee, 2003; Kim et al, 2003; Lanjuin et al, 2003) It is curious why C. elegans lost the typical telomeric dsDNA-binding proteins while retaining the typical telomeric DNA sequence and how they maintain telomeric functions without these telomeric proteins. Our findings suggest that DTN-1 and DTN-2 are bona fide telomeric dsDNA-binding proteins in C. elegans and that they are indispensable for the maintenance of germline immortality and telomere length homeostasis
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