REPLICATION STRUCTURE OF THE HUMAN BETA-GLOBIN GENE DOMAIN
REPLICATION STRUCTURE OF THE HUMAN BETA-GLOBIN GENE DOMAIN
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DOI：
10.1038/366588a0
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发表时间：
1993-12-09
期刊：
影响因子：
64.8
通讯作者：
CEDAR, H
中科院分区：
文献类型：
--
作者：
KITSBERG, D;SELIG, S;CEDAR, H
动物细胞基因组被组织成一系列平均大小为 50-300 kilobases1 的复制子；这些单位中的每一个都有其自己的复制起点，作为 DNA 合成的起始点。在动物病毒中，起点的使用可以通过顺式作用元件来调节2，并且在某些情况下，复制可能是细胞类型特异性的3。然而，人们对内源组织特异性基因复制的组织和控制知之甚少。为了理解这个过程，我们使用复制方向测定来检查覆盖人类β-样珠蛋白结构域的200多个碱基的DNA片段，并确定了位于β-珠蛋白本身上游的单个双向起点。该基因座用于启动表达细胞中的 DNA 合成，其中珠蛋白结构域复制较早，而在非表达细胞中则用于启动 DNA 合成，非表达细胞的特点是相同区域的复制较晚4,5。删除该起始序列（如血红蛋白 Lepore 综合征6 中发生的情况）会取消该位点的双向 DNA 合成，并导致该位点上游的复制方向发生显着逆转。这代表了动物细胞中存在特定的、离散的复制起点的第一个遗传证据。
THE animal cell genome is organized into a series of replicons with an average size of 50-300 kilobases1; each of these units is characterized by its own origin of replication which serves as the point of initiation for DNA synthesis. In animal viruses, origin usage can be regulated by cis-acting elements2, and in some cases, replication may be cell-type specific3. Little is known, however, about the organization and control of endogenous tissue-specific gene replication. To understand this process, we have used a replication direction assay to examine DNA fragments covering more than 200 kilobases of the human beta-like globin domain, and have identified a single bidirectional origin located upstream of the beta-globin itself. This locus is used to initiate DNA synthesis in expressing cells, where the globin domain replicates early, and in non-expressing cells, which are characterized by late replication of the same region4,5. Deletion of this origin sequence, as occurs in the haemoglobin Lepore syndrome6, cancels bidirectional DNA synthesis at this site and leads to a striking reversal of replication direction upstream to the locus. This represents the first genetic proof of the existence of specific, discrete origins of replication in animal cells.