ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation
ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation
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DOI：
10.4161/cc.3.12.1286
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发表时间：
2004-12-01
期刊：
影响因子：
4.3
通讯作者：
Campisi, J
中科院分区：
文献类型：
--
作者：
Davalos, AR;Kaminker, P;Campisi, J
BLM解旋酶是DNA复制过程中最佳修复所必需的，它是一种显著增加人类癌症发病率的缺陷。我们发现，由于DNA损伤反应激酶ATR和ATM的活性，BLM迅速从PML核体移动到受损的复制叉，几小时后返回PML小体。免疫荧光和细胞分级显示，复制应激后，BLM分裂为不同的亚细胞室。出乎意料的是，缺乏BLM的成纤维细胞缺乏磷酸化ATM(S-1981)和53结合蛋白-1(53BP1)，这些蛋白在复制应激后无法形成焦点。表达显性突变型P53或缺乏解旋酶的BLm可恢复复制应激诱导的53BP1焦点，但只有突变型P53可恢复最佳ATM激活。因此，对受损的复制叉状损伤的最佳修复可能需要ATR和ATM。BLM在这些病变中招募53BP1，而不依赖于其解旋酶活性，而ATM的最佳激活需要P53和BLM解旋酶活性。
The BLM helicase, a deficiency that markedly increases cancer incidence in humans, is required for optimal repair during DNA replication. We show that BLM rapidly moves from PML nuclear bodies to damaged replication forks, returning to PML bodies several hours later, owing to activities of the DNA damage response kinases ATR and ATM, respectively. Immunofluorescence and cellular fractionation demonstrate that BLM partitions to different sub-cellular compartments after replication stress. Unexpectedly, fibroblasts lacking BLM were deficient in phospho-ATM (S-1981) and 53-binding protein-1 (53BP1), and these proteins failed to form foci following replication stress. Expression of a dominant p53 mutant or helicase-deficient BLM restored replication stress-induced 53BP1 foci, but only mutant p53 restored optimal ATM activation. Thus, optimal repair of damaged replication fork lesions likely requires both ATR and ATM. BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities.