Telomere uncapping during in vitro T-lymphocyte senescence.
Normal lymphocytes represent examples of somatic cells that are able to induce telomerase activity when stimulated. As previously reported, we showed that, during lymphocyte long-term culture and repeated stimulations, the appearance of senescent cells is associated with telomere shortening and a progressive drop in telomerase activity. We further showed that this shortening preferentially occured at long telomeres and was interrupted at each stimulation by a transitory increase in telomere length. In agreement with the fact that telomere uncapping triggers lymphocyte senescence, we observed an increase in gamma-H2AX and 53BP1 foci as well as in the percentage of cells exhibiting DNA damage foci in telomeres. Such a DNA damage response may be related to the continuous increase of p16(ink4a) upon cell stimulation and cell aging. Remarkably, at each stimulation, the expression of shelterin genes, such as hTRF1, hTANK1, hTIN2, hPOT1 and hRAP1, was decreased. We propose that telomere dysfunction during lymphocyte senescence caused by iterative stimulations does not only result from an excessive telomere shortening, but also from a decrease in shelterin content. These observations may be relevant for T-cell biology and aging.
Chebel
Amel
A
Université Claude Bernard Lyon, CNRS UMR ENS - HCL, Oullins, France.
Bauwens
Serge
S
Gerland
Luc-Marie
LM
Belleville
Aurélie
A
Urbanowicz
Iwona
I
de Climens
Aude Roborel
AR
Tourneur
Yves
Y
Chien
Wei Wen
WW
Catallo
Régine
R
Salles
Gilles
G
Gilson
Eric
E
Ffrench
Martine
M
D000368:Aged; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D006657:Histones / Q000097:blood; D006801:Humans; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000089804:Shelterin Complex; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure*; D034501:Telomere-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000089804:Shelterin Complex; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D019098:Telomerase