Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance.
Telomeres are essential for maintaining cellular proliferative capacity and their loss has been implicated in ageing. A key regulator in telomere maintenance is the telomeric protein TRF1, which was also identified as Pin2 in a screen for Pin1. Pin1 is a unique prolyl isomerase that regulates protein conformation and function after phosphorylation. However, little is known about the role of Pin1 in telomere regulation or the modulation of TRF1 by upstream signals. Here we identify TRF1 as a major conserved substrate for Pin1 during telomere maintenance and ageing. Pin1 inhibition renders TRF1 resistant to protein degradation, enhances TRF1 binding to telomeres, and leads to gradual telomere loss in human cells and in mice. Pin1-deficient mice also show widespread premature ageing phenotypes within just one generation, similar to those in telomerase-deficient mice after 4-5 consecutive generations. Thus, Pin1 is an essential regulator of TRF1 stability, telomere maintenance and ageing.
Lee
Tae Ho
TH
Cancer Biology Program and Biology of Aging Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
Tun-Kyi
Adrian
A
Shi
Rong
R
Lim
Jormay
J
Soohoo
Christina
C
Finn
Greg
G
Balastik
Martin
M
Pastorino
Lucia
L
Wulf
Gerburg
G
Zhou
Xiao Zhen
XZ
Lu
Kun Ping
KP
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000172:deficiency / Q000235:genetics; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D035321:Telomeric Repeat Binding Protein 1; D019098:Telomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse