title: A beginning of the end: new insights into the functional organization of telomeres.
abstract: 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 3' 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.
authors.affiliation: a Department of Cell and Molecular Biology; Feinberg School of Medicine; Northwestern University ; Chicago , IL , USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Wood
authors.forename: Kyle
authors.initials: K
authors.lastname: Laster
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Rice
authors.forename: Steven T
authors.initials: ST
authors.lastname: Kosak
mesh_terms: D002455:Cell Division; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000089804:Shelterin Complex; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism; D059506:Telomere Shortening; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D006570:Heterochromatin; C494847:LMNA protein, human; D034904:Lamin Type A; D000089804:Shelterin Complex; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; C509186:TERT protein, human; D019098:Telomerase
keywords: aging; chromosome looping; chromosome structure; genome stability; nuclear lamina; telomere