Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0660, USA.
Departments of Medicine, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0660, USA.
Nat Commun. 2021 Sep 22;12(1):5568. doi: 10.1038/s41467-021-25866-z.
Eukaryotic DNA Mismatch Repair (MMR) involves redundant exonuclease 1 (Exo1)-dependent and Exo1-independent pathways, of which the Exo1-independent pathway(s) is not well understood. The exo1Δ440-702 mutation, which deletes the MutS Homolog 2 (Msh2) and MutL Homolog 1 (Mlh1) interacting peptides (SHIP and MIP boxes, respectively), eliminates the Exo1 MMR functions but is not lethal in combination with rad27Δ mutations. Analyzing the effect of different combinations of the exo1Δ440-702 mutation, a rad27Δ mutation and the pms1-A99V mutation, which inactivates an Exo1-independent MMR pathway, demonstrated that each of these mutations inactivates a different MMR pathway. Furthermore, it was possible to reconstitute a Rad27- and Msh2-Msh6-dependent MMR reaction in vitro using a mispaired DNA substrate and other MMR proteins. Our results demonstrate Rad27 defines an Exo1-independent eukaryotic MMR pathway that is redundant with at least two other MMR pathways.
真核生物 DNA 错配修复（MMR）涉及冗余的核酸外切酶 1（Exo1）依赖性和 Exo1 非依赖性途径，其中 Exo1 非依赖性途径（s）尚未得到很好的理解。exo1Δ440-702 突变，缺失 MutS Homolog 2（Msh2）和 MutL Homolog 1（Mlh1）相互作用肽（SHIP 和 MIP 盒，分别），消除了 Exo1 MMR 功能，但与 rad27Δ 突变结合并不致命。分析不同组合的 exo1Δ440-702 突变、rad27Δ 突变和 pms1-A99V 突变（失活 Exo1 非依赖性 MMR 途径）的效果，表明这些突变中的每一种都失活了不同的 MMR 途径。此外，使用错配 DNA 底物和其他 MMR 蛋白，有可能在体外重建 Rad27 和 Msh2-Msh6 依赖性 MMR 反应。我们的结果表明 Rad27 定义了一种 Exo1 非依赖性真核 MMR 途径，该途径与至少两种其他 MMR 途径冗余。
