Common Chromosome Fragile Sites in Human and Murine Epithelial Cells and FHIT/FRA3B Loss-Induced Global Genome Instability
Common Chromosome Fragile Sites in Human and Murine Epithelial Cells and FHIT/FRA3B Loss-Induced Global Genome Instability
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DOI：
10.1002/gcc.22097
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发表时间：
2013-11-01
影响因子：
3.7
通讯作者：
Huebner, Kay
中科院分区：
文献类型：
--
作者：
Hosseini, Seyed Ali;Horton, Susan;Huebner, Kay
淋巴母细胞和成纤维细胞中常见脆弱位点的染色体位置不同，位置取决于这些位点的表观遗传学确定的复制起点密度。由于脆弱基因座的重排和相关的脆弱基因产物的丢失是癌症的标志，因此我们的目的是绘制上皮细胞中常见的脆弱位点，大多数癌症都源自上皮细胞。人类上皮细胞中五个最频繁激活的位点是染色体带 2q33 和 Xq22.1，它们不在淋巴母细胞或成纤维细胞中鉴定的最脆弱位点之列。 16q23 处的 FRA16D 是所检查的人类上皮细胞中前三个脆弱位点之一，与淋巴母细胞和成纤维细胞中一样，而淋巴母细胞中最脆弱位点 3p14.2 处的 FRA3B 在大多数测试的上皮细胞系中并不脆弱。上皮细胞表现出不同层次的脆弱部位；一些常见的上皮细胞脆弱位点在上皮癌中显然不经常改变，并且在上皮癌中经常缺失的位点不一定是最脆弱的。由于我们已经报道 FRA3B 编码的 FHIT 蛋白表达缺失会导致复制应激诱导的 DNA 损伤增加，因此我们还检查了 FHIT 缺陷对上皮细胞中基因组不稳定性标记的影响。 FHIT 缺陷细胞在 G1 期细胞中表现出脆性断裂以及 H2AX 和 53BP1 灶的增加，证实在上皮细胞中 FHIT 基因和包含的 FRA3B 是维持基因组稳定性所必需的看护基因。 (c) 2013 年 Wiley 期刊公司。
Chromosomal positions of common fragile sites differ in lymphoblasts and fibroblasts, with positions dependent on the epigenetically determined density of replication origins at these loci. Because rearrangement of fragile loci and associated loss of fragile gene products are hallmarks of cancers, we aimed to map common fragile sites in epithelial cells, from which most cancers derive. Among the five most frequently activated sites in human epithelial cells were chromosome bands 2q33 and Xq22.1, which are not among top fragile sites identified in lymphoblasts or fibroblasts. FRA16D at 16q23 was among the top three fragile sites in the human epithelial cells examined, as it is in lymphoblasts and fibroblasts, while FRA3B at 3p14.2, the top fragile locus in lymphoblasts, was not fragile in most epithelial cell lines tested. Epithelial cells exhibited varying hierarchies of fragile sites; some frequent epithelial cell fragile sites are apparently not frequently altered in epithelial cancers and sites that are frequently deleted in epithelial cancers are not necessarily among the most fragile. Since we have reported that loss of expression of the FRA3B-encoded FHIT protein causes increased replication stress-induced DNA damage, we also examined the effect of FHIT-deficiency on markers of genome instability in epithelial cells. FHIT-deficient cells exhibited increases in fragile breaks and in H2AX and 53BP1 foci in G1 phase cells, confirming in epithelial cells that the FHIT gene and encompassing FRA3B, is a caretaker gene necessary for maintenance of genome stability. (c) 2013 Wiley Periodicals, Inc.