Okazaki fragment maturation: nucleases take centre stage.
Okazaki fragment maturation: nucleases take centre stage.
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DOI：
10.1093/jmcb/mjq048
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发表时间：
2011-02
影响因子：
5.5
通讯作者：
Li Zheng;B. Shen
中科院分区：
文献类型：
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作者：
Li Zheng;B. Shen
在哺乳动物细胞中，完成后链DNA合成需要在每个细胞周期中处理多达5000万个冈崎片段。即使在酵母中，冈崎片段成熟在单轮DNA复制中发生大约一百万次。因此，有效处理冈崎片段对DNA复制和细胞增殖至关重要。在这个过程中，引物合成的RNA/DNA引物被移除，冈崎片段被连接成一个完整的滞后链DNA。RNA/DNA引物的加工需要一组以皮瓣核酸内切酶1 （flap endonucase 1, FEN1）为代表的结构特异性核酸酶。在这里，我们总结了这些核酸酶在不同途径中去除RNA/DNA引物的不同作用。最近的研究结果表明，冈崎片段的成熟是高度协调的。聚合酶δ、FEN1和DNA连接酶I与增殖细胞核抗原的动态相互作用使这些酶在冈崎片段成熟过程中依次发挥作用。这种蛋白-蛋白相互作用可能受到翻译后修饰的调节。我们还讨论了使用突变小鼠模型的研究，这些研究表明，在冈崎片段成熟的不同步骤中，缺陷引起了两种不同的癌症病因机制。影响RNA引物去除效率的突变可能导致未结扎切口和DNA双链断裂的积累。这些DNA链断裂可引起不同形式的染色体畸变，导致与非整倍体和总体染色体重排相关的癌症的发展。另一方面，破坏编辑聚合酶α结合错误的突变导致癌症表现出强烈的突变表型。
Completion of lagging strand DNA synthesis requires processing of up to 50 million Okazaki fragments per cell cycle in mammalian cells. Even in yeast, the Okazaki fragment maturation happens approximately a million times during a single round of DNA replication. Therefore, efficient processing of Okazaki fragments is vital for DNA replication and cell proliferation. During this process, primase-synthesized RNA/DNA primers are removed, and Okazaki fragments are joined into an intact lagging strand DNA. The processing of RNA/DNA primers requires a group of structure-specific nucleases typified by flap endonuclease 1 (FEN1). Here, we summarize the distinct roles of these nucleases in different pathways for removal of RNA/DNA primers. Recent findings reveal that Okazaki fragment maturation is highly coordinated. The dynamic interactions of polymerase δ, FEN1 and DNA ligase I with proliferating cell nuclear antigen allow these enzymes to act sequentially during Okazaki fragment maturation. Such protein-protein interactions may be regulated by post-translational modifications. We also discuss studies using mutant mouse models that suggest two distinct cancer etiological mechanisms arising from defects in different steps of Okazaki fragment maturation. Mutations that affect the efficiency of RNA primer removal may result in accumulation of unligated nicks and DNA double-strand breaks. These DNA strand breaks can cause varying forms of chromosome aberrations, contributing to development of cancer that associates with aneuploidy and gross chromosomal rearrangement. On the other hand, mutations that impair editing out of polymerase α incorporation errors result in cancer displaying a strong mutator phenotype.