Unrepaired clustered DNA lesions induce chromosome breakage in human cells

Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with b...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 108; no. 20; pp. 8293 - 8298
Main Authors Asaithamby, Aroumougame, Hu, Burong, Chen, David J
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 17.05.2011
National Acad Sciences
Subjects
Biological Sciences
Biophysics
Carcinogenesis
Cell Cycle
Cell Division
Cells
Cells, Cultured
Chromosome aberrations
Chromosome Breakage
Chromosomes
Deoxyribonucleic acid
DNA
DNA Damage
DNA Repair
Epithelial cells
Fibroblasts
Fibroblasts - ultrastructure
G2 Phase
genome
Genomes
Human subjects
Humans
Ionizing radiation
Irradiation
Kinetics
Lesions
Mitosis
Radiation
Radiation damage
Spatial distribution
Tissue Distribution
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Summary:Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling, that the kinetics of loss of clustered DNA lesions was substantially compromised in human fibroblasts. The unique spatial distribution of different types of DNA lesions within the clustered damages, but not the physical location of these damages within the subnuclear domains, determined the cellular ability to repair the damage. We then examined checkpoint arrest mechanisms and yield of gross chromosomal aberrations. Induction of nonrepairable clustered damage affected only G2 accumulation but not the early G2/M checkpoint. Further, cells that were released from the G2/M checkpoint with unrepaired clustered damage manifested a spectrum of chromosome aberrations in mitosis. Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis.
Bibliography:http://dx.doi.org/10.1073/pnas.1016045108
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Author contributions: A.A. and D.J.C. designed research; A.A. and B.H. performed research; D.J.C. contributed new reagents/analytic tools; A.A., B.H., and D.J.C. analyzed data; and A.A. wrote the paper.
Edited by Susan S. Wallace, University of Vermont, Burlington, VT, and accepted by the Editorial Board April 1, 2011 (received for review October 25, 2010)
2Present address: Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1016045108