Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Mol Cell. 2013 Feb 7;49(3):536-46. doi: 10.1016/j.molcel.2012.11.016. Epub 2012 Dec 20.
Damaged DNA is an obstacle during DNA replication and a cause of genome instability and cancer. To bypass this problem, eukaryotes activate DNA damage tolerance (DDT) pathways that involve ubiquitylation of the DNA polymerase clamp proliferating cell nuclear antigen (PCNA). Monoubiquitylation of PCNA mediates an error-prone pathway by recruiting translesion polymerases, whereas polyubiquitylation activates an error-free pathway that utilizes undamaged sister chromatids as templates. The error-free pathway involves recombination-related mechanisms; however, the factors that act along with polyubiquitylated PCNA remain largely unknown. Here we report that the PCNA-related 9-1-1 complex, which is typically linked to checkpoint signaling, participates together with Exo1 nuclease in error-free DDT. Notably, 9-1-1 promotes template switching in a manner that is distinct from its canonical checkpoint functions and uncoupled from the replication fork. Our findings thus reveal unexpected cooperation in the error-free pathway between the two related clamps and indicate that 9-1-1 plays a broader role in the DNA damage response than previously assumed.
受损的 DNA 是 DNA 复制过程中的一个障碍，也是基因组不稳定和癌症的一个原因。为了克服这个问题，真核生物激活了 DNA 损伤容忍 (DDT) 途径，该途径涉及 DNA 聚合酶夹增殖细胞核抗原 (PCNA) 的泛素化。PCNA 的单泛素化通过招募跨损伤聚合酶来介导易错途径，而多泛素化则激活了利用未受损的姐妹染色单体作为模板的无差错途径。无差错途径涉及重组相关机制；然而，与多泛素化 PCNA 一起起作用的因素在很大程度上仍然未知。在这里，我们报告说，与 PCNA 相关的 9-1-1 复合物通常与检查点信号有关，与 Exo1 核酸酶一起参与无差错 DDT。值得注意的是，9-1-1 以一种与经典检查点功能不同且与复制叉解耦的方式促进模板转换。因此，我们的研究结果揭示了这两个相关夹之间无差错途径的意外合作，并表明 9-1-1 在 DNA 损伤反应中的作用比之前认为的更为广泛。
