title: Preferential extension of short telomeres induced by low extracellular pH.
abstract: The majority of tumor cells overcome proliferative limit by expressing telomerase. Whether or not telomerase preferentially extends the shortest telomeres is still under debate. When human cancer cells are cultured at neutral pH, telomerase extends telomeres in telomere length-independent manner. However, the microenvironment of tumor is slightly acidic, and it is not yet known how this influences telomerase action. Here, we examine telomere length homeostasis in tumor cells cultured at pHe 6.8. The results indicate that telomerase preferentially extends short telomeres, such that telomere length distribution narrows and telomeres become nearly uniform in size. After growth at pHe 6.8, the expression of telomerase, TRF1, TRF2 and TIN2 decreases, and the abundance of Cajal bodies decreases. Therefore, telomerase are insufficient for extending every telomere and shorter telomeres bearing less shelterin proteins are more accessible for telomerase recruitment. The findings support the 'protein-counting mechanism' in which extended and unextended state of telomere is determined by the number of associated shelterin proteins and the abundance of telomerase. Decreased expression of telomerase and preferential extension of short telomeres have important implications for tumor cell viability, and generate a strong rationale for research on telomerase-targeted anti-cancer therapeutics.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha 410073, China Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510006, P. R. China.
authors.forename: Yuanlong
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Huaihai Institute of Technology, Lianyungang 222005, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha 410073, China.
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha 410073, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ma
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Junjiu
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha 410073, China zhaoy82@mail.sysu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000089804:Shelterin Complex; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; D019098:Telomerase