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

AUTOR(ES)

Pichierri, Pietro

FONTE

Nature Publishing Group

RESUMO

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.

Documentos Relacionados

• BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination
• Multiple pathways process stalled replication forks
• RecA protein promotes the regression of stalled replication forks in vitro
• PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination
• Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein