title: Effect of radiation quality on mutagenic joining of enzymatically-induced DNA double-strand breaks in previously irradiated human cells.
abstract: Previous work has shown that high charge and energy particle irradiation of human cells evokes a mutagenic repair phenotype, defined by increased mutagenic repair of new double-strand breaks that are introduced enzymatically, days or weeks after the initial irradiation. The effect was seen originally with 600 MeV/u (56)Fe particles, which have a linear energy transfer (LET) value of 174 keV/μm, but not with X rays or γ rays (LET ≤ 2 keV/μm). To better define the radiation quality dependence of the phenomenon, we tested two ions with intermediate LET values, 1,000 MeV/u (48)Ti (LET = 108 keV/μm) and 300 MeV/u (28)Si (LET = 69 keV/μm). These experiments used a previously validated assay, where a rare-cutting nuclease introduces double-strand breaks in two reporter transgene cassettes, which are located on different chromosomes. Deletions of a block of sequence in one of the cassettes, or translocations between cassettes, are measured independently using a multicolor fluorescence assay. The results showed that (48)Ti was a potent, but transient, inducer of mutagenic repair, based on increased frequency of nuclease-induced translocations. The (48)Ti ions did not affect the frequency of nuclease-induced deletions. The (28)Si ions had no measurable effect on either endpoint. There was a close correlation between the induction of the mutagenic repair phenomenon and the frequency of micronuclei in the targeted population (R(2) = 0.74), whereas there was no apparent correlation with radiation-induced cell inactivation. Together, these results better define the radiation quality dependence of the mutagenic repair phenomenon and establish its correlation, or lack of correlation, with other endpoints.
authors.affiliation: a  Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Zhentian
authors.initials: Z
authors.lastname: Li
authors.forename: Huichen
authors.initials: H
authors.lastname: Wang
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.forename: John P
authors.initials: JP
authors.lastname: Murnane
authors.forename: William S
authors.initials: WS
authors.lastname: Dynan
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D006801:Humans; D018499:Linear Energy Transfer; D048629:Micronuclei, Chromosome-Defective; D009154:Mutation