Trends in Cell Biology
ReviewSpecial Issue: Chromatin DynamicsAssembly of telomeric chromatin to create ALTernative endings
Section snippets
Targeting telomeres in cancer
Telomeres are the terminal nucleoprotein structures located at the ends of eukaryotic chromosomes. These structures function as guardians of genome stability by limiting unwanted DNA repair activity at chromosome ends, and in human cells, by controlling the total number of times a cell can divide, thereby limiting the accumulation of genomic instability in actively cycling cells [1].
Genome preservation is orchestrated by the telomere nucleoprotein structure through the functions of the
ALT associated mutations in histone H3, ATRX, and DAXX
The first evidence that epigenetic and chromatin dysfunction participate in ALT came from a study of PanNET and GBM tumors [14]. These tumors contained large clustered telomeric foci, as detected by fluorescence in situ hybridization (FISH), that were reminiscent of ALT-associated PML bodies (APBs). The same tumors also invariably lacked detectable expression of ATRX and often DAXX [14]. This remarkable correlation between ALT and deregulated ATRX expression was further substantiated by the
A distinctive chromatin landscape at ALT telomeres
Mammalian telomeric chromatin appears to have several structural features that make it different from other regions. Telomeric DNA is typically organized into regularly spaced, tightly packed nucleosomes that have a shorter (40 bp) linker DNA segment between nucleosomes [37], perhaps owing to a paucity of linker binding histone H1 [38]. Biochemical studies have shown that the TTAGGG repeat is an inherently poor substrate for nucleosome assembly [39] and once assembled, telomeric nucleosomes,
Repair of DNA damage at ALT telomeres
Cells that utilize ALT almost exclusively lack p53, exhibit complex karyotype rearrangements, extensive micronucleation, and impaired DNA repair capacity that is consistent with an inherently unstable genome [20]. This is evident by the persistence of irreparable DNA damage foci and spontaneous colocalization of telomeric DNA and DNA damage repair factors that form foci termed telomere-dysfunction induced foci (TIFs), which are present in both APB and non-APB foci [60]. The fact that these TIFs
Concluding remarks
We have discussed recent developments in the area of ALT telomere biology and the new interest in the relationship between chromatin dysfunction and the activation of ALT. It is becoming clearer that telomere function is particularly sensitive to changes in chromatin structure and post-translational histone modifications. Although many unresolved issues remain (Box 2), the complementation of innovative proteomic and molecular biology tools with new cellular imaging technologies will undoubtedly
Acknowledgments
We apologize to all those whose work we were unable to refer to in this review due to space constraints. We thank Justin Roncaioli, Louise D’Cruz (University of Pittsburgh, Pittsburgh, USA), Zachary Gurard Levin (Institute Curie, Paris, France), and Anthony Cesare (CMRI, Sydney, Australia) for critical reading and for input into the manuscript. We thank Tadgh O’Tuama for assistance with graphics. R.O.S. is supported by the University of Pittsburgh Cancer Institute. G.A. is supported by la Ligue
Glossary
- Chromatin remodeler
- ATP driven molecular machines that alter chromatin structure by sliding, ejecting, or restructuring nucleosomes. For example, ATRX associates with histone H3 to maintain higher order chromatin structure.
- DNA methyltransferase
- A class of enzymes that catalyze the transfer of a methyl group to cytosine or guanine residues, altering gene expression and recruiting heterochromatin related proteins to the region.
- Extrachromosomal TTAGGG repeats (ECTR)
- Telomeric DNA repeats which are
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