ALAN D'ANDREA, MD
DANA-FARBER CANCER INSTITUTE

Dr. D'Andrea received his MD in 1983 from Harvard Medical School, residency training in pediatrics at Children's Hospital of Philadelphia, and fellowship training in pediatric hematology-oncology at DFCI and Children's Hospital Boston (CHB). He completed a research fellowship at the Whitehead Institute and joined DFCI in 1990. He is also scientific director of the DFCI Molecular Diagnostics Laboratory and director of the Clinical Gene Therapy Center at CHB.

Recent Awards:
• Award of Merit, Fanconi Anemia Scientific Symposium 2002
• E. Mead Johnson Award for Research in Pediatrics, Society for Pediatric Research 2001
• Excellence in Research Award, American Academy of Pediatrics 1997

Research - Chromosome Instability and Susceptibility to Cancer

Dr. D'Andrea's laboratory examines the molecular signaling pathways which regulate the DNA damage response in mammalian cells. Disruption of these pathways, by germline or somatic mutation, leads to genomic instability, cellular sensitivity to ionizing radiation, and defective cell cycle checkpoints and DNA repair. These pathways are often disrupted in cancer cells, accounting for the chromosome instability and increased mutation frequency in human tumors. Their primary focus is the molecular pathogenesis of the human chromosome instability syndromes: Fanconi anemia (FA), ataxia-telangiectasia (AT), and Bloom syndrome (BS). FA is an autosomal-recessive cancer susceptibility disorder characterized by developmental defects and increased cellular sensitivity to DNA crosslinking agents. Seven FA genes have been cloned, and the encoded FA proteins interact in a novel signaling pathway. Five FA proteins (A, C, E, F, G) form a nuclear protein complex required for the monoubiquitination of the D2 protein. Activated D2 is targeted to chromatin, where it interacts with the BRCA1 and BRCA2 breast-cancer susceptibility gene products. Our research program addresses several aspects of this novel signaling pathway, including (1) the assembly, transport, and structure of the FA protein complex; (2) the enzymatic monoubiquitination and deubiquitination of the D2 protein; (3) the function of the chromatin-associated FA complex in cell cycle checkpoints and homologous recombination DNA repair; and (4) the identification of novel interacting proteins in these complexes.