DNA polymerase zeta: new insight into eukaryotic mutagenesis and mammalian embryonic development.
DNA polymerase zeta: new insight into eukaryotic mutagenesis and mammalian embryonic development.
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DOI：
10.3748/wjg.v9.i6.1165
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发表时间：
2003-06
影响因子：
4.3
通讯作者：
F. Zhu;M. Zhang
中科院分区：
文献类型：
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作者：
F. Zhu;M. Zhang
有关真核生物突变机制的信息可能有助于了解人类健康问题，例如基因毒性和癌症。真核突变主要是内源性和环境因素攻击的结果。除了DNA修复、细胞周期检查点和DNA损伤避免之外，细胞还进化出了DNA损伤耐受机制，在复制过程中，特定的DNA聚合酶可能会在基因组中发生针对损伤的突变，以绕过损伤（跨损伤DNA合成，TLS），或者可能诱导未损伤的DNA模板发生突变（非靶向突变）。 DNA聚合酶zeta（pol zeta）首先在芽殖酵母酿酒酵母中发现，由催化亚基scRev3和刺激亚基scRev7组成，近年来受到越来越多的关注。 Pol zeta是DNA聚合酶eta亚家族的成员，属于DNA聚合酶B家族，几乎存在于所有真核生物中。 scRev3 基因的人类同源物位于染色体区域 6q21，而小鼠的同源物映射到 10 号染色体，位于 c-myb 基因的远端并靠近 Macs 基因。选择性剪接、上游框架外 ATG 可以在酵母 scRev3、小鼠和人类同源物中找到。此外，AUG起始密码子上游253-323的序列有可能在REV3 mRNA中形成茎环发夹二级结构，表明人REV3蛋白在正常生长条件下可能在人细胞中低水平表达。功能域分析表明酵母Rev3-980保守区II中的酪氨酸位于聚合酶活性位点。人REV3氨基酸残基1 776-2 195提供REV7结合结构域，并且REV7氨基酸残基1-211提供REV1、REV3和REV7本身的结合结构域。更有趣的是，REV7 与 hMAD2 相互作用，因此可能通过影响 APC（后期促进复合物）的激活来发挥细胞周期控制的作用。目前已知pol zeta参与哺乳动物中大多数自发突变、通过TLS的病变靶向突变、化学致癌物诱导的非靶向突变和抗体基因的体细胞超突变。在 TLS 途径中，pol zeta 与其他 DNA 聚合酶（例如 pol iota）组合，充当“错配延伸剂”。与酵母不同，最近发现 pol zeta 在小鼠胚胎发育中也发挥作用。据推测，pol zeta 在 TLS 和细胞周期控制中的作用可能导致小鼠胚胎致死。
Information about the mechanisms that generate mutations in eukaryotes is likely to be useful for understanding human health concerns, such as genotoxicity and cancer. Eukaryotic mutagenesis is largely the outcome of attacks by endogenous and environmental agents. Except for DNA repair, cell cycle checkpoints and DNA damage avoidance, cells have also evolved DNA damage tolerance mechanism, by which lesion-targeted mutation might occur in the genome during replication by specific DNA polymerases to bypass the lesions (translesion DNA synthesis, TLS), or mutation on undamaged DNA templates (untargeted mutation) might be induced. DNA polymerase zeta (pol zeta), which was found firstly in budding yeast Saccharomyces cerevisiae and consists of catalytic subunit scRev3 and stimulating subunit scRev7, has received more attention in recent years. Pol zeta is a member of DNA polymerase eta subfamily, which belongs to DNA polymerase B family, and exists in almost all eukaryotes. Human homolog of the scRev3 gene is located in chromosome region 6q21, and the mouse equivalent maps to chromosome 10, distal to the c-myb gene and close to the Macs gene. Alternative splicing, upstream out-of frame ATG can be found in yeast scRev3, mouse and human homologs. Furthermore, the sequence from 253-323 immediate upstream of the AUG initiator codon has the potential to form a stem-loop hairpin secondary structure in REV3 mRNA, suggesting that human REV3 protein may be expressed at low levels in human cells under normal growth conditions. The functional domain analysis showed that yeast Rev3-980 tyrosine in conserved region II is at the polymerase active site. Human REV3 amino acid residues 1 776-2 195 provide a REV7 binding domain, and REV7 amino acid residues 1-211 provide a bind domain for REV1, REV3 and REV7 itself. More interestingly, REV7 interacts with hMAD2 and therefore might function in the cell cycle control by affecting the activation of APC (anaphase promoting complex). Currently it has been known that pol zeta is involved in most spontaneous mutation, lesion-targeted mutation via TLS, chemical carcinogen induced untargeted mutation and somatic hypermutation of antibody genes in mammalian. In TLS pathway, pol zeta acts as a "mismatch extender" with combination of other DNA polymerases, such as pol iota. Unlike in yeast, it was found that pol zeta also functioned in mouse embryonic development more recently. It was hypothesized that the roles of pol zeta in TLS and cell cycle control might contribute to mouse embryonic lethality.