Common chromosomal fragile site FRA16D sequence:: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells
Common chromosomal fragile site FRA16D sequence:: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells
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DOI：
10.1093/hmg/9.11.1651
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发表时间：
2000-07-01
影响因子：
3.5
通讯作者：
Richards, RI
中科院分区：
文献类型：
--
作者：
Ried, K;Finnis, M;Richards, RI
DNA亚克隆的瓷砖路径的荧光原位杂交以前已经实现了最小DNA序列的细胞遗传学定义，该序列跨越了FRA16D常见的染色体脆弱位点，位于16q23.2。在胃，结肠，肺和卵巢的腺癌中，据报道了FRA16D基因座的纯合缺失。我们已经对含有FRA16D脆弱部位和肿瘤细胞中纯合区域的最小纯合区域进行了测序。该序列使某些肿瘤细胞断裂点可以定位到包含与FRA10B和FRA16B稀有位点相似的区域的区域。 FRA16D DNA序列还导致鉴定出以（脆弱的位点FRA16D氧化还原酶）命名的剪接基因，其外显子均跨越了脆弱的位点和纯合缺失的最小区域。此外，内含子含FRA16D的完整DNA序列没有显示其他正宗转录本的证据。或者对转录本进行了剪接（对于I，对于II和III）编码具有N末端WW结构域并且在其C末端不同的蛋白质，对于III，具有截短的氧化还原酶域。与FRA16D相关的缺失选择性影响基因转录本。多发性骨髓瘤的五个先前映射的易位断点中的三个也位于For基因内。因此，是16q23.2 DNA不稳定性的主要遗传靶标，而用于功能的扰动可能会导致癌细胞中FRA16D DNA不稳定性的生物学后果。
Fluorescence in situ hybridization of a tile path of DNA subclones has previously enabled the cytogenetic definition of the minimal DNA sequence which spans the FRA16D common chromosomal fragile site, located at 16q23.2. Homozygous deletion of the FRA16D locus has been reported in adenocarcinomas of stomach, colon, lung and ovary. We have sequenced the 270 kb containing the FRA16D fragile site and the minimal homozygously deleted region in tumour cells. This sequence enabled localization of some of the tumour cell breakpoints to regions which contain AT-rich secondary structures similar to those associated with the FRA10B and FRA16B rare fragile sites. The FRA16D DNA sequence also led to the identification of an alternatively spliced gene, named FOR (fragile site FRA16D oxidoreductase), exons of which span both the fragile site and the minimal region of homozygous deletion. In addition, the complete DNA sequence of the FRA16D-containing FOR intron reveals no evidence of additional authentic transcripts. Alternatively spliced FOR transcripts (FOR I, FOR II and FOR III) encode proteins which share N-terminal WW domains and differ at their C-terminus, with FOR III having a truncated oxidoreductase domain. FRA16D-associated deletions selectively affect the FOR gene transcripts. Three out of five previously mapped translocation breakpoints in multiple myeloma are also located within the FOR gene. FOR is therefore the principle genetic target for DNA instability at 16q23.2 and perturbation of FOR function is likely to contribute to the biological consequences of DNA instability at FRA16D in cancer cells.