1. ¹Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
2. ²Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
3. ³Department of Pediatrics, Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Correspondence: Dr SI Wells, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, TCHRF Room S7-206, Cincinnati, OH 45229, USA. E-mail: Susanne.Wells@cchmc.org

Received 3 December 2007; Revised 17 March 2008; Accepted 17 March 2008; Published online 28 April 2008.

Abstract

Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes—in addition to FA gene mutation—may promote FA-related human cancer.