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Journal of Biomedicine and Biotechnology
Volume 2008 (2008), Article ID 821529, 8 pages
http://dx.doi.org/10.1155/2008/821529
Research Article

Biomarkers and Mechanisms of FANCD2 Function

1Laboratory of Cellular & Molecular Radiation Oncology, Department of Radiation Oncology, Massachusetts General Hospital, Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA
2Laboratory of Radiobiology and Experimental Radiation Oncology, University Hospital Eppendorf, University of Hamburg, 20246 Hamburg, Germany
3Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA

Received 26 November 2007; Accepted 25 February 2008

Academic Editor: Lisa Wiesmuller

Copyright © 2008 Henning Willers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Genetic or epigenetic inactivation of the pathway formed by the Fanconi anemia (FA) and BRCA1 proteins occurs in several cancer types, making the affected tumors potentially hypersensitive to DNA cross-linkers and other chemotherapeutic agents. It has been proposed that the inability of FA/BRCA-defective cells to form subnuclear foci of effector proteins, such as FANCD2, can be used as a biomarker to aid individualization of chemotherapy. We show that FANCD2 inactivation not only renders cells sensitive to cross-links, but also oxidative stress, a common effect of cancer therapeutics. Oxidative stress sensitivity does not correlate with FANCD2 or RAD51 foci formation, but associates with increased H2AX foci levels and apoptosis. Therefore, FANCD2 may protect cells against cross-links and oxidative stress through distinct mechanisms, consistent with the growing notion that the pathway is not linear. Our data emphasize the need for multiple biomarkers, such as H2AX, FANCD2, and RAD51, to capture all pathway activities.