4.1 Article

A beginning of the end: new insights into the functional organization of telomeres

Journal

NUCLEUS
Volume 6, Issue 3, Pages 172-178

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/19491034.2015.1048407

Keywords

aging; chromosome structure; chromosome looping; genome stability; nuclear lamina; telomere

Categories

Funding

  1. Ellison Medical Foundation New Scholar Award
  2. NIH New innovator Award [DP2 OD008717-01]
  3. American Cancer Society [PF-13-004-01-CCG]

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Ever since the first demonstration of their repetitive sequence and unique replication pathway, telomeres have beguiled researchers with how they function in protecting chromosome ends. Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 30 overhang into telomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms of chromosome end-structure that may implicate telomere organization in cellular processes beyond its essential role in telomere protection and homeostasis. In particular, we have recently described that t-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termed interstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, a canonical component of the nucleoskeleton that is mutated in myriad human diseases, including human segmental progeroid syndromes. Since ITLs are associated with telomere stability and require functional lamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence induced by telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Here we speculate on other potential ramifications of ITL formation, from gene expression to genome stability to chromosome structure.

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