Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
Mol Cell. 2010 Nov 24;40(4):619-31. doi: 10.1016/j.molcel.2010.10.024. Epub 2010 Nov 4.
Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisomerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.
基因组完整性每次受到 DNA 复制叉停滞或崩溃的威胁。在这里，我们报告了一种由 MMS22L（C6ORF167）和 TONSL（NFKBIL2）组成的复合物的鉴定，该复合物参与了复制应激的恢复。MMS22L 和 TONSL 分别与酵母 Mms22 和植物 Tonsoku/Brushy1 同源。MMS22L-TONSL 在与受损复制叉或加工 DNA 断裂相关的 ssDNA 区域积累，其耗尽会导致高水平的内源性 DNA 双链断裂，因为在复制叉崩溃后无法完成 DNA 合成。此外，耗尽 MMS22L 的细胞对喜树碱（一种拓扑异构酶 I 抑制剂，可损害 DNA 复制进展）高度敏感。最后，MMS22L 和 TONSL 是 DNA 损伤后 RAD51 焦点有效形成所必需的，其耗尽会损害同源重组。这些结果表明，MMS22L 和 TONSL 是基因组守护者，可刺激停滞或崩溃的复制叉的重组依赖性修复。
