TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends.
Telomeres protect the ends of linear genomes, and the gradual loss of telomeres is associated with cellular ageing. Telomere protection involves the insertion of the 3' overhang facilitated by telomere repeat-binding factor 2 (TRF2) into telomeric DNA, forming t-loops. We present evidence suggesting that t-loops can also form at interstitial telomeric sequences in a TRF2-dependent manner, forming an interstitial t-loop (ITL). We demonstrate that TRF2 association with interstitial telomeric sequences is stabilized by co-localization with A-type lamins (lamin A/C). We also find that lamin A/C interacts with TRF2 and that reduction in levels of lamin A/C or mutations in LMNA that cause an autosomal dominant premature ageing disorder--Hutchinson Gilford Progeria Syndrome (HGPS)-lead to reduced ITL formation and telomere loss. We propose that cellular and organismal ageing are intertwined through the effects of the interaction between TRF2 and lamin A/C on chromosome structure.
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Ashley M
AM
Wood
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Jannie M
JM
Rendtlew Danielsen
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Catherine A
CA
Lucas
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Ellen L
EL
Rice
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
David
D
Scalzo
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Takeshi
T
Shimi
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Robert D
RD
Goldman
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Erica D
ED
Smith
Section of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois 60637, USA.
Michelle M
MM
Le Beau
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Steven T
ST
Kosak
D016922:Cellular Senescence / Q000502:physiology; D002877:Chromosomes, Human / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000502:physiology*; D011371:Progeria / Q000209:etiology; D035182:TATA Box Binding Protein-Like Proteins / Q000502:physiology*; D016615:Telomere / Q000502:physiology
D034904:Lamin Type A; D035182:TATA Box Binding Protein-Like Proteins; C441409:TBPL1 protein, human; C440308:lamin C