title: Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.
abstract: Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.
authors: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China; Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, China.
authors: Weiguang
authors: W
authors: Qiang
authors: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China; Department of Radiation Oncology, Changzhou Tumor Hospital, Soochow University, Changzhou, China.
authors: Qinqin
authors: Q
authors: Wu
authors: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors: Fuxiang
authors: F
authors: Zhou
authors: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors: Conghua
authors: C
authors: Xie
authors: Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, China. Electronic address: wcpzlk@163.com.
authors: Changping
authors: C
authors: Wu
authors: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China. Electronic address: yfzhouwhu@163.com.
authors: Yunfeng
authors: Y
authors: Zhou
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D015536:Down-Regulation; D017353:Gene Deletion; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D034622:RNA Interference; D011836:Radiation Tolerance; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics* / Q000473:pathology / Q000528:radiation effects; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C495876:ACD protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase
keywords: ALT; Osteosarcoma; Radiosensitivity; TPP1; Telomere