Abstract
Bloom's syndrome (BS) arises through mutations in both copies of the BLM gene that encodes a RecQ 3′-5′ DNA helicase. BS patients are predisposed to developing all the cancers that affect the general population, and BS cells exhibit marked genetic instability. We showed recently that BLM protein contributes to the cellular response to ionizing radiation by acting as downstream ATM kinase effector. We now show that following UVC treatment, BLM-deficient cells exhibit a reduction in the number of replicative cells, a partial escape from the G2/M cell cycle checkpoint, and have an altered p21 response. Surprisingly, we found that hydroxyurea-treated BLM-deficient cells exhibit an intact S phase arrest, proper recovery from the S phase arrest, and intact p53 and p21 responses. We also show that the level of BLM falls sharply in response to UVC radiation. This UVC-induced reduction in BLM does not require a functional ATM gene and does not result from a subcellular compartment change. Finally, we demonstrate that exposure to UVC and hydroxyurea treatment both induce BLM phosphorylation via an ATM-independent pathway. These results are discussed in the light of their potential physiological significance with regard to the role of BLM in the cellular pathways activated by UVC radiation or HU-mediated inhibition of DNA synthesis.
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Abbreviations
- BrdU:
-
Bromodeoxyuridine
- BS:
-
Bloom's syndrome
- CFSE:
-
Carboxyfluorescein succinimidyl ester
- DSBs:
-
Double-strand breaks
- FITC:
-
Fluorescein isothiocyanate
- PI:
-
Propidium iodide
- SCE:
-
Sister chromatid exchange
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Acknowledgements
We would like to thank Catherine Durieux (UMR 1598 CNRS, Villejuif) for her expert assistance in FACS analysis. We also thank Christian Jaulin (CNRS UPR 1142, IGH, Montpellier) for invaluable stimulating discussions and critical reading of the manuscript. This work was supported by funds and/or fellowships from the Centre National de la Recherche Scientifique, the Association pour la Recherche sur le Cancer (ARC 9660 and 5419, to Mounira Amor-Guéret), the Fondation pour la Recherche Médicale, the Fondation de France and the Ligue Nationale contre le Cancer (Comité de Val de Marne). Mouna Ababou is a recipient of a fellowship from the Ligue Nationale contre le Cancer (Comité de la Haute-Marne) and Virginie Dumaire is a recipient of a fellowship from the Ecole Nationale Supérieure de Cachan.
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Ababou, M., Dumaire, V., Lécluse, Y. et al. Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition. Oncogene 21, 2079–2088 (2002). https://doi.org/10.1038/sj.onc.1205246
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DOI: https://doi.org/10.1038/sj.onc.1205246
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