Turker M S, Gage B M, Rose J A, Elroy D, Ponomareva O N, Stambrook P J, Tischfield J A
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201, USA.
Cancer Res. 1999 Apr 15;59(8):1837-9.
To determine the types of mutations induced by oxidative damage, a kidney cell line with a heterozygous deficiency for the autosomal Aprt (adenine phosphoribosyltransferase) gene was tested for its mutagenic response to hydrogen peroxide. Aprt-deficient cells were selected and scored for loss of heterozygosity (LOH) for 11 microsatellite loci on mouse chromosome 8. On the basis of the LOH analysis, spontaneous mutants (n = 38) were distributed into four classes: apparent point mutation, mitotic recombination, chromosome loss, and large interstitial deletion. However, 9 of 20 (45%) hydrogen peroxide-induced mutants exhibited a novel class of mutations characterized by "discontinuous LOH" for one or more of the microsatellite loci. Interestingly, mutations resembling discontinuous LOH are commonly observed in a wide variety of human cancers. Our data suggest that discontinuous LOH is a signature mutational pattern for oxidative damage and further suggest that such genetic damage is widespread in cancer.
为了确定氧化损伤诱导的突变类型，对常染色体腺嘌呤磷酸核糖转移酶（Aprt）基因杂合缺失的肾细胞系进行了过氧化氢诱变反应测试。选择Aprt缺陷细胞，并对小鼠8号染色体上11个微卫星位点的杂合性缺失（LOH）进行评分。基于LOH分析，自发突变体（n = 38）分为四类：明显的点突变、有丝分裂重组、染色体丢失和大的间质缺失。然而，20个过氧化氢诱导的突变体中有9个（45%）表现出一种新型突变，其特征是一个或多个微卫星位点出现“间断性LOH”。有趣的是，在多种人类癌症中通常会观察到类似间断性LOH的突变。我们的数据表明，间断性LOH是氧化损伤的标志性突变模式，进一步表明这种基因损伤在癌症中广泛存在。
