title: Biomarkers and mechanisms of FANCD2 function.
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 gammaH2AX 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 gammaH2AX, FANCD2, and RAD51, to capture all pathway activities.
authors.affiliation: Laboratory of Cellular & Molecular Radiation Oncology, Department of Radiation Oncology, Massachusetts General Hospital, Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kachnic
authors.forename: Chen-Mei
authors.initials: CM
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Purschke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Held
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D051135:Rad51 Recombinase / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C468783:H2AX protein, human; D006657:Histones; C495153:RAD51 protein, human; D051135:Rad51 Recombinase