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首页> 外文期刊>Molecular and Cellular Biology >Illegitimate recombination leading to allelic loss and unbalanced translocation in p53-mutated human lymphoblastoid cells.
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Illegitimate recombination leading to allelic loss and unbalanced translocation in p53-mutated human lymphoblastoid cells.

机译：非法重组导致p53突变的人类淋巴母细胞中的等位基因丢失和不平衡易位。

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摘要

Allelic loss and translocation are critical mutational events in human tumorigenesis. Allelic loss, which is usually identified as loss of heterozygosity (LOH), is frequently observed at tumor suppressor loci in various kinds of human tumors. It is generally thought to result from deletion or mitotic recombination between homologous chromosomes. In this report, we demonstrate that illegitimate (nonhomologous) recombination strongly contributes to the generation of allelic loss in p53-mutated cells. Spontaneous and X-ray-induced LOH mutations at the heterozygous thymidine kinase (tk) gene, which is located on the long arm of chromosome 17, from normal (TK6) and p53-mutated (WTK-1) human lymphoblastoid cells were cytogenetically analyzed by chromosome 17 painting. We observed unbalanced translocations in 53% of LOH mutants spontaneously arising from WTK-1 cells but none spontaneously arising from TK6 cells. We postulate that illegitimate recombination was occurring between nonhomologous chromosomes after DNA replication, leading to allelic loss and unbalanced translocations in p53-mutated WTK-1 cells. X-ray irradiation, which induces DNA double-strand breaks (DSBs), enhanced the generation of unbalanced translocation more efficiently in WTK-1 than in TK6 cells. This observation implicates the wild-type p53 protein in the regulation of homologous recombination and recombinational DNA repair of DSBs and suggests a possible mechanism by which loss of p53 function may cause genomic instability.
机译：等位基因的丢失和易位是人类肿瘤发生中的关键突变事件。通常在各种人类肿瘤的肿瘤抑制基因座上观察到等位基因缺失，通常被鉴定为杂合性缺失（LOH）。通常认为这是由于同源染色体之间的缺失或有丝分裂重组所致。在此报告中，我们证明了非法（非同源）重组在p53突变细胞中强烈促进等位基因丢失的产生。细胞遗传学分析了正常（TK6）和p53突变（WTK-1）人淋巴母细胞的杂合胸苷激酶（tk）基因的自发和X射线诱导的LOH突变，该基因位于第17号染色​​体的长臂上由17号染色​​体绘画。我们观察到53％的LOH突变体的不平衡易位是由WTK-1细胞自发产生的，而没有自发地由TK6细胞产生。我们假设DNA复制后非同源染色体之间发生非法重组，导致等位基因丢失和p53突变的WTK-1细胞中的不平衡易位。 X射线辐射诱导DNA双链断裂（DSB），在WTK-1中比在TK6细胞中更有效地增强了不平衡易位的产生。该观察结果表明野生型p53蛋白参与了DSBs的同源重组和重组DNA修复的调控，并暗示了p53功能丧失可能导致基因组不稳定的可能机制。

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