caa a22 4500 606175229 CHVBK 20210128100742.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00018-014-1783-0 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1783-0 Topoisomerase II inhibition suppresses the proliferation of telomerase-negative cancers [Elektronische Daten] [Meng-Hsun Hsieh, Cheng-Hui Tsai, Chuan-Chuan Lin, Tsai-Kun Li, Ting-Wei Hung, Li-Te Chang, Ling-Wei Hsin, Shu-Chun Teng] Telomere maintenance is required for chromosome stability, and telomeres are typically elongated by telomerase following DNA replication. In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. Previous studies have indicated that yeast Sgs1 and Top3 may work together to remove highly negative supercoils that are generated from recombination. However, the mechanism by which cells eradicate highly positive supercoils during recombination remains unclear. In the present study, we demonstrate that TOP2 is involved in telomere-telomere recombination. Disturbance of telomeric structure by RIF1 or RIF2 deletion alleviates the requirement for TOP2 in telomere-telomere recombination. In human telomerase-negative alternative lengthening of telomere (ALT) cells, TOP2α or TOP2β knockdown decreases ALT-associated PML bodies, increases telomere dysfunction-induced foci and triggers telomere shortening. Similar results were observed when ALT cells were treated with ICRF-193, a TOP2 inhibitor. Importantly, ICRF-193 treatment blocks ALT-associated phenotypes in vitro, causes telomere shortening, and inhibits ALT cell proliferation inmice. Taken together, these findings imply that TOP2 is involved in the ALT pathway, perhaps by resolving the highly positive supercoil structure at the front of the helicase. Inhibition of topoisomerase II may be a promising therapeutic approach that can be used to prevent cell proliferation in ALT-type cancer cells. Springer Basel, 2014 ICRF-193 nationallicence Telomere nationallicence Alternative lengthening of telomeres nationallicence Recombination nationallicence ALT : Alternative lengthening of telomeres nationallicence APBs : ALT-associated PML bodies nationallicence TIFs : Telomere dysfunction-induced foci nationallicence BIR : Break-induced replication nationallicence SD : Standard deviation nationallicence Hsieh Meng-Hsun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut Tsai Cheng-Hui Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut Lin Chuan-Chuan Department of Food Science, China University of Science and Technology, 115, Taipei, Taiwan aut Li Tsai-Kun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut Hung Ting-Wei Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut Chang Li-Te Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, 100, Taipei, Taiwan aut Hsin Ling-Wei Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, 100, Taipei, Taiwan aut Teng Shu-Chun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut Cellular and Molecular Life Sciences Springer Basel 72/9(2015-05-01), 1825-1837 1420-682X 72:9<1825 2015 72 18 https://doi.org/10.1007/s00018-014-1783-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1783-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hsieh Meng-Hsun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Tsai Cheng-Hui Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Lin Chuan-Chuan Department of Food Science, China University of Science and Technology, 115, Taipei, Taiwan aut NATIONALLICENCE 700 1- Li Tsai-Kun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Hung Ting-Wei Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chang Li-Te Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Hsin Ling-Wei Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, 100, Taipei, Taiwan aut NATIONALLICENCE 700 1- Teng Shu-Chun Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/9(2015-05-01), 1825-1837 1420-682X 72:9<1825 2015 72 18