Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
Department of Pathology; Brander Cancer Research Institute; New York Medical College; Valhalla, NY USA.
Cell Cycle. 2014;13(1):23-31. doi: 10.4161/cc.27407. Epub 2013 Dec 3.
DNA polymerase δ (Pol δ) is a key enzyme in eukaryotic DNA replication. Human Pol δ is a heterotetramer whose p12 subunit is degraded in response to DNA damage, leading to the in vivo conversion of Pol δ4 to Pol δ3. Two E3 ubiquitin ligases, RNF8 and CRL4(Cdt2), participate in the DNA damage-induced degradation of p12. We discuss how these E3 ligases integrate the formation of Pol δ3 and ubiquitinated PCNA for DNA repair processes. CRL4(Cdt2) partially degrades p12 during normal cell cycle progression, thereby generating Pol δ3 during S phase. This novel finding extends the current view of the role of Pol δ3 in DNA repair and leads to the hypothesis that it participates in DNA replication. The coordinated regulation of licensing factors and Pol δ3 by CRL4(Cdt2) now opens new avenues for control of DNA replication. A parallel study of Pol δ4 and Pol δ3 in Okazaki fragment processing provides evidence for a role of Pol δ3 in DNA replication. We discuss several new perspectives of the role of the 2 forms of Pol δ in DNA replication and repair, as well the significance of the integration of p12 regulation in DNA repair and cell cycle progression.
DNA 聚合酶 δ（Pol δ）是真核生物 DNA 复制的关键酶。人类 Pol δ 是一种异四聚体，其 p12 亚基在 DNA 损伤时被降解，导致体内 Pol δ4 转化为 Pol δ3。两种 E3 泛素连接酶，RNF8 和 CRL4（Cdt2），参与 p12 的 DNA 损伤诱导降解。我们讨论了这些 E3 连接酶如何整合 Pol δ3 的形成和泛素化 PCNA 以进行 DNA 修复过程。CRL4（Cdt2）在正常细胞周期进展过程中部分降解 p12，从而在 S 期生成 Pol δ3。这一新颖的发现扩展了 Pol δ3 在 DNA 修复中的作用的现有观点，并导致假设它参与 DNA 复制。CRL4（Cdt2）对许可因子和 Pol δ3 的协调调节现在为控制 DNA 复制开辟了新途径。对 Okazaki 片段加工中的 Pol δ4 和 Pol δ3 的平行研究为 Pol δ3 在 DNA 复制中的作用提供了证据。我们讨论了 Pol δ 的这两种形式在 DNA 复制和修复中的作用的几个新观点，以及 p12 调节在 DNA 修复和细胞周期进展中的整合的意义。
