Department of Blood Transfusion and Clinical Lab, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Genetic Testing Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Gene. 2023 Jan 30;851:147029. doi: 10.1016/j.gene.2022.147029. Epub 2022 Nov 7.
The DNA polymerase delta (Pol δ), a heterotetramer of four subunits (Pol δ4), plays a pivotal role in DNA replication, as well as in DNA damage repair. Pold4, as the smallest subunit of Pol δ, is degraded in response to DNA damage or when entering into S-phase. This leads to the conversion of Pol δ4 to the trimeric complex Pol δ3. 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 δ3 but not Pol δ4 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.
DNA 聚合酶 delta（Pol δ）是一个由四个亚基组成的异四聚体（Pol δ4），在 DNA 复制以及 DNA 损伤修复中发挥着关键作用。Pold4 作为 Pol δ 的最小亚基，在 DNA 损伤或进入 S 期时会被降解，从而导致 Pol δ4 转化为三聚体复合物 Pol δ3。然而，在哺乳动物中，Pold4 的作用尚未完全阐明。Schizosaccharomyces pombe 中的 Pold4 同源物 Cdm1 对于细胞生长和 DNA 损伤修复不是必需的，而 Saccharomyces cerevisiae 中则没有 Pold4 同源物。我们之前生成了 Pold3 的敲除小鼠模型，揭示了其在基因组稳定性中的重要作用。出乎意料的是，我们发现 Pold4 敲除小鼠是存活且可育的。此外，Pold4 敲除小鼠的肺和脾组织（Pold4 表达最丰富的组织）没有任何病理变化。此外，Pold4 敲除小鼠尾尖成纤维细胞（TTF）的细胞生长、细胞周期、DNA 复制、DNA 损伤和 DNA 修复能力均正常。这些结果表明，Pol δ3 而不是 Pol δ4 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）小鼠肝脏有肿瘤，而 Pold4 敲除小鼠没有，并且 Pold4 敲除小鼠的寿命增加。进一步的研究为 Pold4 可能成为肺癌的一个潜在新靶点提供了证据，因为其缺失不会影响正常细胞，但会影响癌细胞。
