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Nucleic Acids Res. 2015 Jul 27;43(13):6334-47. doi: 10.1093/nar/gkv598. Epub 2015 Jun 16.

Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death.

Author information

1
School of Medicine, Tsinghua University, No. 1 Tsinghua Yuan, Haidian District, Beijing 100084, China University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics; University of Pittsburgh School of Medicine; 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
2
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics; University of Pittsburgh School of Medicine; 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA Xiangya Hospital, Central South University, Changsha, 410000, China.
3
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; 5117 Centre Avenue, Pittsburgh, PA 15213, USA Departments of Medicine and Bioengineering, University of Pittsburgh, 3550 Terrace Street, 1218 Scaife Hall, Pittsburgh, PA 15261, USA.
4
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics; University of Pittsburgh School of Medicine; 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
5
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine. W1340 Biomedical Science Tower 3, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
6
School of Medicine, Tsinghua University, No. 1 Tsinghua Yuan, Haidian District, Beijing 100084, China Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, 1905 V.A. Drive, 306 Health Science Research Building, Lexington, KY 40536, USA.
7
Xiangya Hospital, Central South University, Changsha, 410000, China Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China Department of Immunobiology and Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
8
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; 5117 Centre Avenue, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics; University of Pittsburgh School of Medicine; 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA lil64@pitt.edu.

Abstract

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.

PMID:
26082495
PMCID:
PMC4513870
DOI:
10.1093/nar/gkv598
[Indexed for MEDLINE]
Free PMC Article

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