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

doi:10.1083/jcb.200110009

Published online 26 March 2002. doi:10.1083/jcb.200110009

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© The Rockefeller University Press, 0021-9525/2002/4/19 $5.00
The Journal of Cell Biology, Volume 157, Number 1, April 1, 2002 19-30

Article

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

Annapaola Franchitto and Pietro Pichierri

Laboratorio di Citogenetica Molecolare e Mutagenesi, DABAC, Università della Tuscia, 01100 Viterbo, Italy

Address correspondence to Pietro Pichierri, 94801 Villejuif, France. Tel.: 33-1-4958-3409. Fax: 33-1-4958-3411. E-mail: pichier{at}vjf.cnrs.fr

Bloom's syndrome (BS) is a rare genetic disorder characterizedby a broad range of symptoms and, most importantly, a predispositionto many types of cancers. Cells derived from patients with BSexhibit an elevated rate of somatic recombination and hypermutability,supporting a role for bleomycin (BLM) in the maintenance ofgenomic integrity. BLM is thought to participate in severalDNA transactions, the failure of which could give raise to genomicinstability, and to interact with many proteins involved inreplication, recombination, and repair. In this study, we showthat BLM function is specifically required to properly relocalizethe RAD50/MRE11/NBS1 (RMN) complex at sites of replication arrest,but is not essential in the activation of BRCA1 either afterstalled replication forks or ${gamma}$ -rays. We also provide evidencethat BLM is phosphorylated after replication arrest in an Ataxiaand RAD3-related protein (ATR)-dependent manner and that phosphorylationis not required for subnuclear relocalization. Therefore, inATR dominant negative mutant cells, the assembly of the RMNcomplex in nuclear foci after replication blockage is almostcompletely abolished. Together, these results suggest a relationshipbetween BLM, ATR, and the RMN complex in the response to replicationarrest, proposing a role for BLM protein and RMN complex inthe resolution of stalled replication forks.

Key Words: BLM; RecQ helicases; replication arrest; recombination; MRE11

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