Overview
Research in the Andreassen Laboratory at Cincinnati Children's Hospital Medical Center focuses on the relationship of cell cycle checkpoints to the genetic instability that underlies the development of cancer. In particular, we are studying basic cellular mechanisms involved in the rare disease Fanconi Anemia (FA). FA is characterized by chromosome instability, including both the spontaneous and DNA crosslinker-induced formation of radial chromosomes. Fanconi Anemia is also associated with aplastic anemia, progressive bone marrow failure, and a predisposition to leukemia and other cancers. At present, thirteen FA genes have been identified. The proteins corresponding to these FA genes function in a pathway leading to the monoubiquitination of FANCD2 (at Lysine 561) and these FANCI post-translational modifications are mediated by a nuclear complex containing at least eight of the other FA gene products. FANCD2 is monoubiquitinated both during S phase and in response to DNA damage, and a failure of FANCD2 monoubiquitination is associated with the disease. Importantly, FANCD2 monoubiquitination is normal in three FA complementation groups, FA-D1, FA-J, and FA-N, suggesting that the corresponding gene products function downstream of monoubiquitinated FANCD2. FANCD1 is BRCA2, which has an important role in DNA repair by homologous recombination. FANCJ is BRIP1, a helicase first identified by its association with the BRCA1 tumor suppressor protein.
Areas of Research
An important area of interest is in the lab investigation of mechanisms of regulation that couple FANCD2 monoubiquitination to the DNA damage response. We believe that understanding this regulation will yield insight into the pathogenesis of Fanconi Anemia and the associated predisposition to cancer. The ATR checkpoint kinase is specifically required for DNA damage-induced FANCD2 monoubiquitination. Since ATR coordinates the cellular response to replication stress, this potentially implicates the FA pathway in this process.
Andreassen, P.R., D'Andrea, A.D., and Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004 Aug 15;18(16):1958-63.
Another general area of interest is related to the recent discovery that monoubiquitination targets FANCD2 to chromatin and nuclear foci, where it organizes the tumor suppressor BRCA2/FANCD1 in response to DNA damage. To better understand the function of FANCD2 and the FA pathway, we are investigating the function of FANCD2 DNA damage foci in chromatin and identifying interactions with other components of the DNA damage response.
Wang, X.Z., Andreassen, P.R., and D'Andrea, A.D. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004 Jul;24(13):5850-62.
Montes de Oca, R., Andreassen, P.R., Gregory, R.C., Taniguchi, T., Wang, X., Houghtaling, S., Grompe, M., and D'Andrea, A.D. Regulated interaction of the Fanconi Anemia protein, FANCD2, with chromatin. Blood. 2005 Feb 1;105(3):1003-9.
We are also interested in how BRIP1/BACH1, which was recently identified as FANCJ, interacts with other FA proteins. These studies should be important in elucidating the collective functions of FA proteins in cellular responses to DNA damage, and should better define the functional relationship, if any, of the tumor suppressor BRCA1 to FA proteins.
Cantor SB, Andreassen PR. Assessing the link between BACH1 and BRCA1 in the FA pathway. Cell Cycle. 2006 5:164-167.
