Nucleic Acids Research, 2003, Vol. 31, No. 21 6272-6282
© 2003 Oxford University Press
Possible anti-recombinogenic role of Bloom’s syndrome helicase in double-strand break processing
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8126, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif Cedex, France, 1 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, IPBS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France and 2 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 218, Institut Curie, Section de Recherche, Paris 75248 Cedex 05, France
*To whom correspondence should be addressed. Tel: +33 1 42 11 40 50; Fax: +33 1 42 11 54 94; Email: amor{at}igr.fr
Bloom’s syndrome (BS) which associates genetic instability and predisposition to cancer is caused by mutations in the BLM gene encoding a RecQ family 3'–5' DNA helicase. It has been proposed that the generation of genetic instability in BS cells could result from an aberrant non-homologous DNA end joining (NHEJ), one of the two main DNA double-strand break (DSB) repair pathways in mammalian cells, the second major pathway being homologous recombination (HR). Using cell extracts, we report first that Ku70/80 and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), key factors of the end-joining machinery, and BLM are located in close proximity on DNA and that BLM binds to DNA only in the absence of ATP. In the presence of ATP, BLM is phosphorylated and dissociates from DNA in a strictly DNA-PKcs-dependent manner. We also show that BS cells display, in vivo, an accurate joining of DSBs, reflecting thus a functional NHEJ pathway. In sharp contrast, a 5-fold increase of the HR-mediated DNA DSB repair in BS cells was observed. These results support a model in which NHEJ activation mediates BLM dissociation from DNA, whereas, under conditions where HR is favored, e.g. at the replication fork, BLM exhibits an anti-recombinogenic role.
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