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Cells with dysfunctional telomeres are susceptible to reactive oxygen species hydrogen peroxide via generation of multichromosomal fusions and chromosomal fragments bearing telomeres

Author:
Woo, Seon Rang, Park, Jeong-Eun, Juhn, Kyoung-Mi, Ju, Yeun-Jin, Jeong, Jaemin, Kang, Chang-Mo, Yun, Hyun Jin, Yun, Mi Yong, Shin, Hyun-Jin, Joo, Hyun-Yoo, Park, Eun-Ran, Park, In-Chul, Hong, Sung Hee, Hwang, Sang-Gu, Kim, Haekwon, Cho, Myung-Haing, Kim, Sang Hoon, Park, Gil Hong, Lee, Kee-Ho
Source:
Biochemical and biophysical research communications 2012 v.417 no.1 pp. 204-210
ISSN:
0006-291X
Subject:
DNA damage, DNA repair, acetylcysteine, antioxidants, chromosome aberrations, genotoxicity, hydrogen peroxide, hypersensitivity, telomeres
Abstract:
During genotoxic stress, reactive oxygen species hydrogen peroxide (H₂O₂) 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 H₂O₂, via generation of multichromosomal fusion and chromosomal fragments. H₂O₂ 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 H₂O₂ 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 H₂O₂. 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.
Agid:
895009