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¹ Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720
² Buck Institute for Age Research, Novato, CA 94945

Address correspondence to Judith Campisi, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 84-171, Berkeley, CA 94720. Tel.: (510) 486-4416. Fax: (510) 486-4545. email: jcampisi{at}lbl.gov

Bloom syndrome (BS) is a hereditary disorder characterized by pre- and postnatal growth retardation, genomic instability, and cancer. BLM, the gene defective in BS, encodes a DNA helicase thought to participate in genomic maintenance. We show that BS human fibroblasts undergo extensive apoptosis after DNA damage specifically when DNA replication forks are stalled. Damage during S, but not G₁, caused BLM to rapidly form foci with H2AX at replication forks that develop DNA breaks. These BLM foci recruited BRCA1 and NBS1. Damaged BS cells formed BRCA1/NBS1 foci with markedly delayed kinetics. Helicase-defective BLM showed dominant-negative activity with respect to apoptosis, but not BRCA1/NBS1 recruitment, suggesting catalytic and structural roles for BLM. Strikingly, inactivation of p53 prevented the death of damaged BS cells and delayed recruitment of BRCA1/NBS1. These findings suggest that BLM is an early responder to damaged replication forks. Moreover, p53 eliminates cells that rapidly assemble BRCA1/NBS1 without BLM, suggesting that BLM is essential for timely BRCA1/NBS1 function.

Key Words: DNA damage; DNA repair; DNA replication; H2AX; S phase checkpoint

Abbreviations used in this paper: BS, Bloom syndrome; BSF, Bloom syndrome fibroblast; HM, helicase mutant; HU, hydroxyurea; NHF, normal human fibroblast; PML, promyelocytic leukemia protein.

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