Telomerase enzymatic component hTERT shortens long telomeres in human cells.
Telomere lengths are tightly regulated within a narrow range in normal human cells. Previous studies have extensively focused on how short telomeres are extended and have demonstrated that telomerase plays a central role in elongating short telomeres. However, much about the molecular mechanisms of regulating excessively long telomeres is unknown. In this report, we demonstrated that the telomerase enzymatic component, hTERT, plays a dual role in the regulation of telomere length. It shortens excessively long telomeres and elongates short telomeres simultaneously in one cell, maintaining the optimal telomere length at each chromosomal end for efficient protection. This novel hTERT-mediated telomere-shortening mechanism not only exists in cancer cells, but also in primary human cells. The hTERT-mediated telomere shortening requires hTERT's enzymatic activity, but the telomerase RNA component, hTR, is not involved in that process. We found that expression of hTERT increases telomeric circular DNA formation, suggesting that telomere homologous recombination is involved in the telomere-shortening process. We further demonstrated that shelterin protein TPP1 interacts with hTERT and recruits hTERT onto the telomeres, suggesting that TPP1 might be involved in regulation of telomere shortening. This study reveals a novel function of hTERT in telomere length regulation and adds a new element to the current molecular model of telomere length maintenance.
Cancer Prevention and Control; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Yun-Ling
YL
Zheng
Cancer Biology Division; Washington University School of Medicine; Saint Louis, MO USA.
Fan
F
Zhang
Cancer Prevention and Control; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Bing
B
Sun
Cancer Biology Division; Washington University School of Medicine; Saint Louis, MO USA.
Juan
J
Du
Cancer Biology Division; Washington University School of Medicine; Saint Louis, MO USA.
Chongkui
C
Sun
Medical College; Jinan University; Guangzhou, China.
Jie
J
Yuan
Cancer Prevention and Control; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Ying
Y
Wang
Cancer Prevention and Control; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Lian
L
Tao
Cancer Prevention and Control; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Krishna
K
Kota
Molecular Oncology Programs; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Xuefeng
X
Liu
Molecular Oncology Programs; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA.
Richard
R
Schlegel
Cancer Biology Division; Washington University School of Medicine; Saint Louis, MO USA.
Qin
Q
Yang
D015153:Blotting, Western; D020732:Cytogenetic Analysis; D004270:DNA, Circular / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D059506:Telomere Shortening / Q000502:physiology*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C495876:ACD protein, human; D004270:DNA, Circular; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase
TPP1; hTERT; hTR; length regulation; telomerase; telomere length upper limit; telomeres