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DNA聚合酶δ是早期哺乳动物胚胎发育所必需的。

DNA polymerase delta is required for early mammalian embryogenesis.

作者信息

Uchimura Arikuni, Hidaka Yuko, Hirabayashi Takahiro, Hirabayashi Masumi, Yagi Takeshi

机构信息

Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.

出版信息

PLoS One. 2009;4(1):e4184. doi: 10.1371/journal.pone.0004184. Epub 2009 Jan 15.

DOI:10.1371/journal.pone.0004184
PMID:19145245
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2615215/
Abstract

BACKGROUND

In eukaryotic cells, DNA polymerase delta (Poldelta), whose catalytic subunit p125 is encoded in the Pold1 gene, plays a central role in chromosomal DNA replication, repair, and recombination. However, the physiological role of the Poldelta in mammalian development has not been thoroughly investigated.

METHODOLOGY/PRINCIPAL FINDINGS: To examine this role, we used a gene targeting strategy to generate two kinds of Pold1 mutant mice: Poldelta-null (Pold1(-/-)) mice and D400A exchanged Poldelta (Pold1(exo/exo)) mice. The D400A exchange caused deficient 3'-5' exonuclease activity in the Poldelta protein. In Poldelta-null mice, heterozygous mice developed normally despite a reduction in Pold1 protein quantity. In contrast, homozygous Pold1(-/-) mice suffered from peri-implantation lethality. Although Pold1(-/-) blastocysts appeared normal, their in vitro culture showed defects in outgrowth proliferation and DNA synthesis and frequent spontaneous apoptosis, indicating Poldelta participates in DNA replication during mouse embryogenesis. In Pold1(exo/exo) mice, although heterozygous Pold1(exo/+) mice were normal and healthy, Pold1(exo/exo) and Pold1(exo/-) mice suffered from tumorigenesis.

CONCLUSIONS

These results clearly demonstrate that DNA polymerase delta is essential for mammalian early embryogenesis and that the 3'-5' exonuclease activity of DNA polymerase delta is dispensable for normal development but necessary to suppress tumorigenesis.

摘要

背景

在真核细胞中，DNA聚合酶δ（Poldelta）的催化亚基p125由Pold1基因编码，在染色体DNA复制、修复和重组中起核心作用。然而，Poldelta在哺乳动物发育中的生理作用尚未得到充分研究。

方法/主要发现：为了研究这一作用，我们采用基因靶向策略生成了两种Pold1突变小鼠：Poldelta缺失（Pold1(-/-)）小鼠和D400A交换的Poldelta（Pold1(exo/exo)）小鼠。D400A交换导致Poldelta蛋白的3'-5'核酸外切酶活性缺陷。在Poldelta缺失小鼠中，杂合小鼠尽管Pold1蛋白量减少，但发育正常。相比之下，纯合Pold1(-/-)小鼠在植入前致死。虽然Pold1(-/-)囊胚看起来正常，但它们的体外培养显示出生长增殖和DNA合成缺陷以及频繁的自发凋亡，表明Poldelta参与小鼠胚胎发生过程中的DNA复制。在Pold1(exo/exo)小鼠中，虽然杂合Pold1(exo/+)小鼠正常健康，但Pold1(exo/exo)和Pold1(exo/-)小鼠发生了肿瘤。

结论

这些结果清楚地表明，DNA聚合酶δ对哺乳动物早期胚胎发育至关重要，并且DNA聚合酶δ的3'-5'核酸外切酶活性对于正常发育是可有可无的，但对于抑制肿瘤发生是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/b81e2e650456/pone.0004184.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/9743d156992e/pone.0004184.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/ffecb63dd16a/pone.0004184.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/171a5afe9ff1/pone.0004184.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/76893e6f06a3/pone.0004184.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/b81e2e650456/pone.0004184.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/9743d156992e/pone.0004184.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/ffecb63dd16a/pone.0004184.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/171a5afe9ff1/pone.0004184.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/76893e6f06a3/pone.0004184.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00e6/2615215/b81e2e650456/pone.0004184.g005.jpg

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