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  • The EMBO Journal (2004) 23, 3154 - 3163
  • doi:10.1038/sj.emboj.7600277

Published online: 15 July 2004

BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks

Pietro Pichierri, Annapaola Franchitto and Filippo Rosselli

  1. UPR2169 CNRS, 'Genetic Instability and Cancer', Institut Gustave Roussy, Pavillon de Recherche, Rue Camille Desmoulins, Villejuif, France

Correspondence to:

Pietro Pichierri, UPR2169 CNRS, 'Genetic Instability and Cancer', Institut Gustave Roussy, Pavillon de Recherche #2–3rd floor, room 473, 39, Rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel.: +33 1 4211 5032; Fax: +33 1 4211 5008; E-mail: pichierri70@virgilio.it

Filippo Rosselli, UPR2169 CNRS, 'Genetic Instability and Cancer', Institut Gustave Roussy, Pavillon de Recherche #2–3rd floor, room 473, 39, Rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel.: +33 1 4211 5116; Fax: +33 1 4211 5008; E-mail: rosselli@igr.fr

Received 9 February 2004; Accepted 25 May 2004

Fanconi anaemia (FA) and Bloom syndrome (BS) are autosomal recessive diseases characterised by chromosome fragility and cancer proneness. Here, we report that BLM and the FA pathway are activated in response to both crosslinked DNA and replication fork stall. We provide evidence that BLM and FANCD2 colocalise and co-immunoprecipitate following treatment with either DNA crosslinkers or agents inducing replication arrest. We also find that the FA core complex is necessary for BLM phosphorylation and assembly in nuclear foci in response to crosslinked DNA. Moreover, we show that knock-down of the MRE11 complex, whose function is also under the control of the FA core complex, enhances cellular and chromosomal sensitivity to DNA interstrand crosslinks in BS cells. These findings suggest the existence of a functional link between BLM and the FA pathway and that BLM and the MRE11 complex are in two separated branches of a pathway resulting in S-phase checkpoint activation, chromosome integrity and cell survival in response to crosslinked DNA.

  • Keywords:

    • BLM helicase,
    • DNA repair,
    • Fanconi anaemia,
    • replication fork arrest,
    • S-phase checkpoint