Pold4 is dispensable for mouse development, DNA replication and DNA repair
Pold4 is dispensable for mouse development, DNA replication and DNA repair
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Pold4 对于小鼠发育、DNA 复制和 DNA 修复是不可或缺的
DOI：
10.1016/j.gene.2022.147029
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发表时间：
2022-11-10
期刊：
影响因子：
3.5
通讯作者：
Zhou, Zhongcheng
中科院分区：
文献类型：
--
作者：
Gu, Xueping;Dai, Qinjin;Zhou, Zhongcheng
DNA聚合酶δ（Pol δ）是由四个亚基（Pol δ 4）组成的异源四聚体，在DNA复制和DNA损伤修复中起着关键作用。Pold 4作为Pol delta的最小亚基，在DNA损伤或进入S期时被降解。这导致Pol δ 4转化为三聚体复合物Pol δ 3。然而，Pold 4在哺乳动物中的作用尚未完全阐明。Cdm1是粟酒裂殖酵母中的Pold4直向同源物，在细胞生长和DNA损伤修复中起重要作用，而酿酒酵母中没有Pold4直向同源物。我们先前产生了Pold3的敲除小鼠模型，并揭示了其在基因组稳定性中的重要作用。出乎意料的是，我们在这里发现Pold4敲除小鼠是可行的和可生育的。此外，Pold4敲除小鼠在肺和脾中没有表现出任何病理变化，这些组织具有最丰富的Pold4表达。Pold4基因敲除小鼠尾尖成纤维细胞（TTF）具有正常的细胞生长、细胞周期、DNA复制、DNA损伤和DNA修复能力。这些结果表明，Pol delta 3而不是Pol delta 4可能负责正常细胞中的这些过程。有趣的是，19个月大的野生型（WT）小鼠在肝脏中有肿瘤，而Pold4敲除小鼠没有，Pold4敲除小鼠显示出更长的寿命。此外，这提供的证据表明，Pold4可能是肺癌的潜在新靶点，因为它的耗尽不会影响正常细胞，但会影响癌细胞。
The DNA polymerase delta (Pol delta), a heterotetramer of four subunits (Pol delta 4), plays a pivotal role in DNA replication, as well as in DNA damage repair. Pold4, as the smallest subunit of Pol delta, is degraded in response to DNA damage or when entering into S-phase. This leads to the conversion of Pol delta 4 to the trimeric complex Pol delta 3. However, the contribution of Pold4 has not been fully elucidated in mammals. Cdm1, the Pold4 ortholog in Schizosaccharomyces pombe, is dispensable for cell growth and DNA damage repair, and there are no Pold4 orthologs in Saccharomyces cerevisiae. We previously generated a knockout mouse model of Pold3 and revealed its essential role in genome stability. Unexpectedly, we here found that Pold4 knockout mice are viable and fertile. In addition, Pold4 knockout mice do not exhibit any pathologic changes in the lung and spleen, tissues with the most abundant expression of Pold4. Moreover, Pold4 knockout mouse tail tip fibroblasts (TTF) exhibited normal cell growth, cell cycle, DNA replication, DNA damage and DNA repair capacity. These results suggested that Pol delta 3 but not Pol delta 4 may be responsible for these processes in normal cells. Interestingly, 19-month-old wild-type (WT) mice had tumors in the liver, while Pold4 knockout mice did not, and Pold4 knockout mice showed increased longevity. In further, this provided evidence suggested that Pold4 could be a potential novel target for lung carcinoma because its depletion does not affect normal cells but does affect cancer cells.