title: Chromosomal end fusion resulting from telomere erosion increases susceptibility to radiation via multinucleation: effect of p53.
abstract: Loss of p53 tumor suppressor facilitates acquisition of telomerase activity. In fact, both p53 inactivation and telomerase activation are frequently found in human cancers. p53 inactivation, however, eliminates or attenuates the biological responses to telomerase inhibition and the eventual telomere erosion. We show that telomere erosion can increase the susceptibility to radiation, irrespective of p53 status. Both telomerase inhibition and critically shortened telomere with significant change of chromosomal end-to-end fusion were essential for the enhancement of radiosensitivity. The enhancement was correlated with greater formation of multinucleated cells. p53 inactivation did not eliminate the observed generation of chromosomal fusion and multinucleation, and the resulting increased susceptibility to radiation, as opposed to the previously proved role of p53 in mediating cellular responses to telomere dysfunction. The present findings suggest the importance of chromosomal end fusion in modulating radiosensitivity rather than p53 DNA damage signaling. Thus, the suggested anticancer radiotherapeutic strategy combined with telomerase inhibition could clinically be applicable to cancers, irrespective of p53 status.
authors.affiliation: Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
authors.forename: Yeun-Jin
authors.initials: YJ
authors.lastname: Ju
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Kyoung Mi
authors.initials: KM
authors.lastname: Juhn
authors.forename: Jaemin
authors.initials: J
authors.lastname: Jeong
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Gil-Hong
authors.initials: GH
authors.lastname: Park
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Myung-Haeng
authors.initials: MH
authors.lastname: Cho
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Won-Bong
authors.initials: WB
authors.lastname: Park
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D016923:Cell Death; D002875:Chromosomes / Q000235:genetics*; D042822:Genomic Instability; D051379:Mice; D008938:Mitosis; D011836:Radiation Tolerance / Q000235:genetics; D011995:Recombination, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D019098:Telomerase