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Molecular and Cellular Biology, August 2006, p. 6047-6055, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00444-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

UV Radiation Induces Delayed Hyperrecombination Associated with Hypermutation in Human Cells{dagger}

Stephen T. Durant,1 Kimberly S. Paffett,1 Meena Shrivastav,1 Graham S. Timmins,2 William F. Morgan,3 and Jac A. Nickoloff1*

Department of Molecular Genetics and Microbiology, Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131,1 Toxicology Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131,2 Radiation Oncology Research Laboratory and Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 212013

Received 14 March 2006/ Returned for modification 28 April 2006/ Accepted 2 June 2006

Ionizing radiation induces delayed genomic instability in human cells, including chromosomal abnormalities and hyperrecombination. Here, we investigate delayed genome instability of cells exposed to UV radiation. We examined homologous recombination-mediated reactivation of a green fluorescent protein (GFP) gene in p53-proficient human cells. We observed an ~5-fold enhancement of delayed hyperrecombination (DHR) among cells surviving a low dose of UV-C (5 J/m2), revealed as mixed GFP+/– colonies. UV-B did not induce DHR at an equitoxic (75 J/m2) dose or a higher dose (150 J/m2). UV is known to induce delayed hypermutation associated with increased oxidative stress. We found that hypoxanthine phosphoribosyltransferase (HPRT) mutation frequencies were ~5-fold higher in strains derived from GFP+/– (DHR) colonies than in strains in which recombination was directly induced by UV (GFP+ colonies). To determine whether hypermutation was directly caused by hyperrecombination, we analyzed hprt mutation spectra. Large-scale alterations reflecting large deletions and insertions were observed in 25% of GFP+ strains, and most mutants had a single change in HPRT. In striking contrast, all mutations arising in the hypermutable GFP+/– strains were small (1- to 2-base) changes, including substitutions, deletions, and insertions (reminiscent of mutagenesis from oxidative damage), and the majority were compound, with an average of four hprt mutations per mutant. The absence of large hprt deletions in DHR strains indicates that DHR does not cause hypermutation. We propose that UV-induced DHR and hypermutation result from a common source, namely, increased oxidative stress. These two forms of delayed genome instability may collaborate in skin cancer initiation and progression.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131. Phone: (505) 272-6960. Fax: (505) 272-6029. E-mail: JNickoloff{at}salud.unm.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2006, p. 6047-6055, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00444-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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