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DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

Dmitrieva, Natalia I. and Cui, Kairong and Kitchaev, Daniil A. and Zhao, Keji and Burg, Maurice B. (2011) DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts. Proceedings of the National Academy of Sciences of the United States of America, 108 (51). pp. 20796-20801. ISSN 0027-8424. PMCID PMC3251130.

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High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. The exact nature of the breaks, and their location, has not been entirely clear, and it has not been evident how cells survive, replicate, and maintain genome integrity in environments like the renal inner medulla in which cells are constantly exposed to high NaCl concentration. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. Here, we confirm by specific comet assay and pulsed-field electrophoresis that cells adapted to high NaCl have increased levels of double-strand breaks. Importantly, γH2AX foci that occur during repair of the breaks are nonrandomly distributed in the mouse genome. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double-strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes (“gene deserts”), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation, and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes.

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Additional Information:© 2011 National Academy of Sciences. Contributed by Maurice B. Burg, October 14, 2011 (sent for review November 5, 2010. Published online before print November 21, 2011. We thank Drs. Chris Combs and Daniela Malide at the National Heart, Lung, and Blood Institute (NHLBI) Light Microscopy Core Facility for help with microscopy and images processing and Dr. Iouri Chepelev at the NHLBI Laboratory of Molecular Immunology for assistance with sequencing data analysis. This research was supported by the Intramural Research Programs of the National Institutes of Health, NHLBI. Author contributions: N.I.D., K.Z., and M.B.B. designed research; N.I.D. and K.C. performed research; N.I.D., D.A.K., and M.B.B. analyzed data; and N.I.D. and M.B.B. wrote the paper.
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Subject Keywords:hypertonicity; salt; DNA damage; kidney; mIMCD3 cells
Issue or Number:51
PubMed Central ID:PMC3251130
Record Number:CaltechAUTHORS:20120113-100916878
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:28777
Deposited By: Jason Perez
Deposited On:13 Jan 2012 21:08
Last Modified:02 Jun 2020 20:52

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