title: Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX.
abstract: Activation of telomerase or alternative lengthening of telomeres (ALT) is necessary for tumours to escape from dysfunctional telomere-mediated senescence. Anti-telomerase drugs might be effective in suppressing tumour growth in approximately 85-90% of telomerase-positive cancer cells. However, there are still chances for these cells to bypass drug treatment after switching to the ALT mechanism to maintain their telomere integrity. But the mechanism underlying this switch is unknown. In this study, we used telomerase-positive cancer cells (HTC75) to discover the mechanism of the telomerase-ALT switch by inducing telomere-specific DNA damage, alpha-thalassemia X-linked syndrome protein (ATRX) knockdown and deletion of death associated protein (DAXX). Surprisingly, two important ALT hallmarks in the ALT-like HTC75 cells were observed after treatments: ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal circular DNA of telomeric repeats. Moreover, knocking out hTERT by utilizing the CRISPR/Cas9 technique led to telomere elongation in a telomerase-independent manner in ALT-like HTC75 cells. In summary, this is the first report to show that inducing telomeric DNA damage, disrupting the ATRX/DAXX complex and inhibiting telomerase activity in telomerase-positive cancer cells lead to the ALT switch.
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Yang
authors: Y
authors: Hu
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Guang
authors: G
authors: Shi
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Laichen
authors: L
authors: Zhang
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Feng
authors: F
authors: Li
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Yuanling
authors: Y
authors: Jiang
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Shuai
authors: S
authors: Jiang
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Wenbin
authors: W
authors: Ma
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Yong
authors: Y
authors: Zhao
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Zhou
authors: Z
authors: Songyang
authors: Key Laboratory of Gene Engineering of the Ministry of Education and Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.|Key Laboratory of Reproductive Medicine of Guangdong Province, School of Life Sciences and the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
authors: Junjiu
authors: J
authors: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D019098:Telomerase / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019098:Telomerase; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein