Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest

被引:100
作者
Franchitto, A [1 ]
Pichierri, P [1 ]
机构
[1] Univ Tuscia, DABAC, Lab Citogenet Mol & Mutagenesi, I-01100 Viterbo, Italy
关键词
BLM; RecQ helicases; replication arrest; recombination; MRE11;
D O I
10.1083/jcb.200110009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 gamma-rays. We also provide evidence that BRCA1 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.
引用
收藏
页码:19 / 30
页数:12
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