Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
J Biol Chem. 2011 Jul 22;286(29):26250-7. doi: 10.1074/jbc.M111.235200. Epub 2011 Jun 3.
Genome integrity is maintained by a network of DNA damage response pathways, including checkpoints and DNA repair processes. In Saccharomyces cerevisiae, the BRCT domain-containing protein Rtt107/Esc4 is required for the restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. In addition to its well characterized interaction with the endonuclease Slx4, Rtt107 interacts with a number of other DNA repair and recombination proteins. These include the evolutionarily conserved SMC5/6 complex, which is involved in numerous chromosome maintenance activities, such as DNA repair, chromosome segregation, and telomere function. The interaction between Rtt107 and the SMC5/6 complex was mediated through the N-terminal BRCT domains of Rtt107 and the Nse6 subunit of SMC5/6 and was independent of methyl methane sulfonate-induced damage and Slx4. Supporting a shared function in the DNA damage response, Rtt107 was required for recruitment of SMC5/6 to DNA double strand breaks. However, this functional relationship did not extend to other types of DNA lesions such as protein-bound nicks. Interestingly, Rtt107 was phosphorylated when SMC5/6 function was compromised in the absence of DNA-damaging agents, indicating a connection beyond the DNA damage response. Genetic analyses revealed that, although a subset of Rtt107 and SMC5/6 functions was shared, these proteins also contributed independently to maintenance of genome integrity.
基因组完整性由一系列 DNA 损伤反应途径维持，包括检查点和 DNA 修复过程。在酿酒酵母中，BRCT 结构域蛋白 Rtt107/Esc4 对于成功修复 DNA 损伤后 DNA 复制的重新启动以及细胞对 DNA 损伤剂的抗性是必需的。除了与内切酶 Slx4 的特征相互作用外，Rtt107 还与许多其他 DNA 修复和重组蛋白相互作用。这些包括进化上保守的 SMC5/6 复合物，它参与了许多染色体维持活动，如 DNA 修复、染色体分离和端粒功能。Rtt107 与 SMC5/6 复合物之间的相互作用是通过 Rtt107 的 N 端 BRCT 结构域和 SMC5/6 的 Nse6 亚基介导的，并且独立于甲基甲烷磺酸酯诱导的损伤和 Slx4。支持在 DNA 损伤反应中具有共同功能，Rtt107 被招募到 DNA 双链断裂处需要 SMC5/6。然而，这种功能关系并不延伸到其他类型的 DNA 损伤，如蛋白结合的缺口。有趣的是，当 SMC5/6 功能在没有 DNA 损伤剂的情况下受到损害时，Rtt107 被磷酸化，这表明存在超出 DNA 损伤反应的联系。遗传分析表明，尽管 Rtt107 和 SMC5/6 的部分功能是共享的，但这些蛋白质也独立地有助于基因组完整性的维持。
