Abstract
The ends of eukaryotic chromosomes need to be protected from the activation of a DNA damage response that leads the cell to replicative senescence or apoptosis. In mammals, protection is accomplished by a six-factor complex named shelterin, which organizes the terminal TTAGGG repeats in a still ill-defined structure, the telomere. The stable interaction of shelterin with telomeres mainly depends on the binding of two of its components, TRF1 and TRF2, to double-stranded telomeric repeats. Tethering of TRF proteins to telomeres occurs in a chromatin environment characterized by a very compact nucleosomal organization. In this work we show that binding of TRF1 and TRF2 to telomeric sequences is modulated by the histone octamer. By means of in vitro models, we found that TRF2 binding is strongly hampered by the presence of telomeric nucleosomes, whereas TRF1 binds efficiently to telomeric DNA in a nucleosomal context and is able to remodel telomeric nucleosomal arrays. Our results indicate that the different behavior of TRF proteins partly depends on the interaction with histone tails of their divergent N-terminal domains. We propose that the interplay between the histone octamer and TRF proteins plays a role in the steps leading to telomere deprotection.
Highlights
Telomeres represent the solution to the problems encountered by eukaryotic cells switching from circular to linear chromosomes [1]
We show that the binding behavior in a chromatin environment is different between TRF1 and TRF2 and that this depends on the divergent N-terminal domains of the two proteins and on the histone tails
In this experiment is clearly visible that TRF2 does not bind nucleosomal binding sites at a protein concentration in which TRF1 shows efficient binding to nucleosome core particles (NCPs) and in which all naked DNA is bound by TRF2
Summary
Telomeres represent the solution to the problems encountered by eukaryotic cells switching from circular to linear chromosomes [1]. Due to the need of an RNA primer to start copying DNA, DNA polymerases are unable to entirely replicate eukaryotic genome; in addition, chromosome ends need to form specific protective structures to avoid inappropriate processing by DNA repair enzymes. Telomeres consist of short G-rich sequences repeated in tandem, ending in a single-stranded protrusion named 3 G-overhang; the solution to the telomere erosion problem is provided by the enzyme telomerase, a reverse transcriptase which adds telomeric repeats onto the 3 ends of chromosomes [2]. The ongoing end-erosion results in chromosome fusions and high genomic instability, a state known as crisis, characterized by massive cell death.
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