Researcher Profile
Alan D. D'Andrea, MD
Alvan T. and Viola D. Fuller American Cancer Society Professor of Radiation Oncology, Harvard Medical School
Center/Program
Department
Area of Research
Chromosome Instability and Susceptibility to Cancer
Contact Information
Alan D. D'Andrea, MDDana-Farber Cancer Institute
44 Binney Street
Mayer 641
Boston, MA 02115
Office phone: (617) 632-2112
Fax: (617) 632-5757
E-mail: alan_dandrea@dfci.harvard.edu
Preferred contact method: office phone
Research
Our 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.
Our 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.
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
Biography
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.
Select Publications
- Howlett NG, Taniguchi T, Durkin SG, D'Andrea AD, Glover TW. The Fanconi anemia pathway for the DNA replication stress response at regulation of common fragile site stability. Hum Mol Genet 2005;14:693-701.
- Montes de Oca R, Gregory R, Taniguchi T, Wang X, Andreassen P, Margossian S, Grompe M, Houghtaling S, D'Andrea AD. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood 2005;105:1003-9.
- Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD, Wang ZQ, Jasin M. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc Natl Acad Sci U S A 2005;102:1110-5.
- New HV, Cale CM, Tischkowitz M, Jones A, Telfer P, Veys P, D'Andrea AD, Mathew CG, Hann I. Nijmegen breakage syndrome diagnosed as Fanconi anaemia. Pediatr Blood Cancer 2005;44:494-9.
- Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RV, D'Andrea AD, Bernards R. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 2005;17:331-9.
- Soulier J, Leblanc T, Larghero J, Dastot H, Shimamura A, Guardiola P, Esperou H, Ferry C, Jubert C, Feugeas JP, Henri A, Toubert A, Socie G, Baruchel A, Sigaux F, D'Andrea AD, Gluckman E. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood 2005;105:1329-36.
- Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 2004;18:1958-63.
- Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 2004;24:5850-62.
- D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 2003;3:23-34.
- Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD. Disruption of the Fanconi anemia/BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 2003;9:568-74.
