title: Cells with dysfunctional telomeres are susceptible to reactive oxygen species hydrogen peroxide via generation of multichromosomal fusions and chromosomal fragments bearing telomeres.
abstract: During genotoxic stress, reactive oxygen species hydrogen peroxide (H(2)O(2)) is a prime mediator of the DNA damage response. Telomeres function both to assist in DNA damage repair and to inhibit chromosomal end-to-end fusion. Here, we show that telomere dysfunction renders cells susceptible to H(2)O(2), via generation of multichromosomal fusion and chromosomal fragments. H(2)O(2) caused formation of multichromosomal end-to-end fusions involving more than three chromosomes, preferentially when telomeres were erosive. Interestingly, extensive chromosomal fragmentation (yielding small-sized fragments) occurred only in cells exhibiting such multichromosomal fusions. Telomeres were absent from fusion points, being rather present in the small fragments, indicating that H(2)O(2) cleaves chromosomal regions adjacent to telomeres. Restoration of telomere function or addition of the antioxidant N-acetylcysteine prevented development of chromosomal aberrations and rescued the observed hypersensitivity to H(2)O(2). Thus, chromosomal regions adjacent to telomeres become sensitive to reactive oxygen species hydrogen peroxide when telomeres are dysfunctional, and are cleaved to produce multichromosomal fusions and small chromosomal fragments bearing the telomeres.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Seon Rang
authors.initials: SR
authors.lastname: Woo
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Kyoung-Mi
authors.initials: KM
authors.lastname: Juhn
authors.forename: Yeun-Jin
authors.initials: YJ
authors.lastname: Ju
authors.forename: Jaemin
authors.initials: J
authors.lastname: Jeong
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Yun
authors.forename: Mi Yong
authors.initials: MY
authors.lastname: Yun
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Shin
authors.forename: Hyun-Yoo
authors.initials: HY
authors.lastname: Joo
authors.forename: Eun-Ran
authors.initials: ER
authors.lastname: Park
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Haekwon
authors.initials: H
authors.lastname: Kim
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Gil Hong
authors.initials: GH
authors.lastname: Park
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002455:Cell Division; D002869:Chromosome Aberrations / Q000139:chemically induced*; D016195:G2 Phase; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
chemical_list: C422952:telomerase RNA; D012313:RNA; D006861:Hydrogen Peroxide; D019098:Telomerase; D000111:Acetylcysteine