Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest.
Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest.
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DOI：
10.1083/jcb.200110009
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发表时间：
2002-04-01
期刊：
影响因子：
--
通讯作者：
Pichierri P
中科院分区：
文献类型：
--
作者：
Franchitto A;Pichierri P
布鲁姆综合征(BS)是一种罕见的遗传性疾病，其特征是症状范围广泛，最重要的是，易患多种癌症。来自BS患者的细胞表现出较高的体细胞重组率和高度变异性，支持博莱霉素(BLM)在维持基因组完整性中的作用。BLM被认为参与了几个DNA交易，这些交易的失败可能会增加基因组的不稳定性，并与许多参与复制、重组和修复的蛋白质相互作用。在本研究中，我们证明了BLm功能是在复制停止位点正确重新定位Rad50/Mre11/NBS1(RMN)复合体所必需的，但在复制叉或γ射线停止后BRCA1的激活过程中并不是必需的。我们还提供了证据，证明BLM在复制停止后以共济失调和RAD3相关蛋白(ATR)依赖的方式被磷酸化，并且亚核重新定位不需要磷酸化。因此，在ATR显性阴性突变细胞中，复制阻断后RMN复合体在核灶中的组装几乎完全取消。总之，这些结果表明了BLM、ATR和RMN复合体之间的关系，表明BLM蛋白和RMN复合体在解决复制分叉停滞的问题上发挥了作用。
Bloom's syndrome (BS) is a rare genetic disorder characterized by a broad range of symptoms and, most importantly, a predisposition to many types of cancers. Cells derived from patients with BS exhibit an elevated rate of somatic recombination and hypermutability, supporting a role for bleomycin (BLM) in the maintenance of genomic integrity. BLM is thought to participate in several DNA transactions, the failure of which could give raise to genomic instability, and to interact with many proteins involved in replication, recombination, and repair. In this study, we show that BLM function is specifically required to properly relocalize the RAD50/MRE11/NBS1 (RMN) complex at sites of replication arrest, but is not essential in the activation of BRCA1 either after stalled replication forks or γ-rays. We also provide evidence that BLM is phosphorylated after replication arrest in an Ataxia and RAD3-related protein (ATR)-dependent manner and that phosphorylation is not required for subnuclear relocalization. Therefore, in ATR dominant negative mutant cells, the assembly of the RMN complex in nuclear foci after replication blockage is almost completely abolished. Together, these results suggest a relationship between BLM, ATR, and the RMN complex in the response to replication arrest, proposing a role for BLM protein and RMN complex in the resolution of stalled replication forks.
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影响因子：
56.9
作者：
Cortez, D;Wang, Y;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
10.5
作者：
Guo, ZJ;Kumagai, A;Dunphy, WG
通讯作者：
Dunphy, WG
影响因子：
30.8
作者：
Gangloff, S;Soustelle, C;Fabre, F
通讯作者：
Fabre, F
影响因子：
5.3
作者：
Mirzoeva, OK;Petrini, JHJ
通讯作者：
Petrini, JHJ
DOI：
10.1073/pnas.130182897
发表时间：
2000-07-05
影响因子：
11.1
作者：
Limoli, CL;Giedzinski, E;Cleaver, JE
通讯作者：
Cleaver, JE