BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks.
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.
Pichierri
Pietro
P
UPR2169 CNRS, Genetic Instability and Cancer, Institut Gustave Roussy, Pavillon de Recherche, Rue Camille Desmoulins, Villejuif, France. pichierri70@virgilio.it
Franchitto
Annapaola
A
Rosselli
Filippo
F
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001816:Bloom Syndrome / Q000378:metabolism; D002460:Cell Line; D003432:Cross-Linking Reagents; D004247:DNA / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein; D006801:Humans; D047468:Immunoprecipitation; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D053484:RecQ Helicases
D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D004247:DNA; D000076228:MRE11 Homologue Protein; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases