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 γH2AX 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.
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29 September 2003
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September 29 2003
Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks
Albert R. Davalos,
Albert R. Davalos
1Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720
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Judith Campisi
Judith Campisi
1Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720
2Buck Institute for Age Research, Novato, CA 94945
Search for other works by this author on:
Albert R. Davalos
1Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720
Judith Campisi
1Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720
2Buck 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: [email protected]
The online version of this article includes supplemental material.
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.
Received:
April 03 2003
Accepted:
July 31 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 162 (7): 1197–1209.
Article history
Received:
April 03 2003
Accepted:
July 31 2003
Citation
Albert R. Davalos, Judith Campisi; Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks . J Cell Biol 29 September 2003; 162 (7): 1197–1209. doi: https://doi.org/10.1083/jcb.200304016
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