title: The topoisomerase II catalytic inhibitor ICRF-193 preferentially targets telomeres that are capped by TRF2.
abstract: The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2) or POT1 were treated with ICRF-193 (3 μM, 24 h) or bleomycin (1 μM, 24 h). DNA damage was assayed by combining telomeric DNA staining of a (CCCTAA)n PNA probe with immunofluorescence of 53BP1 to score the rate of telomere colocalization with 53BP1 foci. We found that ICRF-193, but not bleomycin, leads to DNA damage preferentially at telomeres, which can be rescued by TRF2 inhibition. POT1 inhibition exacerbates telomere dysfunction induced by ICRF-193. Thus, ICRF-193 induces damage at telomeres properly capped by TRF2 but not by POT1. These findings are expected to broaden our view on the mechanism by which conventional therapeutic molecules act to eliminate cancer cells and how to use TRF2 and POT1 levels as surrogate markers for anti-topoisomerase II sensitivity.
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and.
authors.forename: Lianxiang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and.
authors.forename: Yaru
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Xing
authors.affiliation: Institut for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice, France; Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France; Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Shanghai, China.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital affiliated to Shanghai Jiaotong University, School of Medicine; Emergency Department, Shanghai Ruijin Hospital North, Shanghai, China; and yj11254@rjh.com.cn luyiming@rjh.com.cn.
authors.forename: Jing
authors.identifier: http://orcid.org/0000-0002-9471-3321
authors.initials: J
authors.lastname: Ye
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D054659:Diketopiperazines; D016503:Drug Delivery Systems / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D010879:Piperazines / Q000008:administration & dosage*; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage*
chemical_list: D054659:Diketopiperazines; D010879:Piperazines; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione
keywords: ICRF-193; POT1; TRF2; telomere; topoisomerase II