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1 Laboratory of Kidney and Electrolyte Metabolism, National Lung and Blood Institute, Bethesda, MD, USA
2 Gene Response Section, Center for Cancer Research, National Caner Institute, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: dmitrien{at}nhlbi.nih.gov.
High NaCl causes DNA double-strand breaks and cell cycle arrest, but the mechanism of its genotoxicity has been unclear. In this study we describe a novel mechanism that contributes to this genotoxicity. The Mre11 exonuclease complex is a central component of DNA damage response. This complex assembles at sites of DNA damage, where it processes DNA ends for subsequent activation of repair and initiates cell cycle checkpoints. However, this does not occur with DNA damage caused by high NaCl. Rather, following high NaCl, Mre11 exits from the nucleus, DNA double-strand breaks accumulate in the S and G2 phases of the cell cycle, and DNA repair is inhibited. Further, the exclusion of Mre11 from the nucleus by high NaCl persists following ultraviolet or ionizing radiation, also preventing DNA repair in response to those stresses, as evidenced by absence of H2AX phosphorylation at places of DNA damage and by impaired repair of damaged reporter plasmids. Activation of chk1 by phosphorylation on Ser345 generally is required for DNA damage-induced cell cycle arrest. However, chk1 does not become phosphorylated during high NaCl-induced cell cycle arrest. Also, high NaCl prevents ionizing and ultraviolet radiation-induced phosphorylation of chk1, but cell cycle arrest still occurs, indicating existence of alternative mechanisms for the S and G2/M delays. DNA breaks that occur normally during processes like DNA replication and transcription, as well damages to DNA induced by genotoxic stresses ordinarily are rapidly repaired. We propose that inhibition of this repair by high NaCl results in accumulation of DNA damage, accounting for the genotoxicity of high NaCl, and that cell cycle delay induced by high NaCl slows accumulation of DNA damage until the DNA damage response network can be reactivated.
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