MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Mol Cell. 2010 Nov 24;40(4):632-44. doi: 10.1016/j.molcel.2010.10.023. Epub 2010 Nov 4.
Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NFκBIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.
芽殖酵母 Mms22 是同源重组（HR）修复停滞或断裂的 DNA 复制叉所必需的。在这里，我们鉴定了一种人类 Mms22 样蛋白（MMS22L）和 MMS22L 相互作用蛋白 NFκBIL2/TONSL。从人类细胞中耗尽 MMS22L 或 TONSL 会导致在 DNA 复制过程中产生高水平的双链断裂（DSBs）。这两种蛋白质都在受到压力的复制叉上积累，并且从细胞中耗尽 MMS22L 或 TONSL 会导致对引起 S 期相关 DSBs 的试剂（如拓扑异构酶（TOP）抑制剂）的超敏反应。在这种情况下，MMS22L 和 TONSL 是 HR 介导的复制叉相关 DSBs 修复所必需的。在耗尽任一蛋白的细胞中，拓扑异构酶 1 抑制剂喜树碱诱导的 DSBs 正常切除，但 RAD51 重组酶的加载存在缺陷。因此，当 DNA 复制叉附近发生非计划 DSBs 时，MMS22L 和 TONSL 对于维持基因组稳定性是必需的。
