Biological and Biomedical Science
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Frederick W. Alt

Department of Genetics
HHMI/Children's Hospital/CBR Institute
Karp 9th Floor, Room 09216
1 Blackfan Circle
Boston, MA 02115
Tel: (617) 919-2539
Fax: (617) 730-0948
Email: alt@enders.tch.harvard.edu
17 postdoctoral fellows, 5 graduate students

 Fred Alt

The broad focus of the Alt laboratory is the elucidation of mechanisms involved in maintenance of genomic stability in mammalian cells. More specifically, the laboratory studies the mechanism and control of antigen receptor variable region gene assembly (VDJ recombination) in developing B and T lymphocytes and the mechanism of immunoglobulin heavy chain class switch recombination (CSR) and somatic hypermutation in activated mature B lymphocytes. Studies of the regulation of these processes involve elucidation of signaling events that lead to their activation, as well as elucidation of cis-acting chromosomal processes that effect accessibility. Some studies employ biochemical approaches to elucidate molecular mechanisms by which the RAG endonuclease (RAG) and Activation Induced Deaminase (AID) function on DNA to initiate, respectively, VDJ recombination and CSR. Other mechanistic studies employ genetic and cytogenetic approaches to study the role of general DNA double strand break (DSB) repair pathways in VDJ recombination and CSR, as well as the interplay of DNA repair and cell cycle checkpoint mechanisms in suppressing genomic instability and cancer. In this context, the laboratory has developed mouse models, based on conditional inactivation of DSB response and checkpoint genes, for B and T cell lymphomas and brain tumors. A major new area of research in the laboratory is elucidation of the function of the mammalian SIRTuin (SIRT1-7) proteins in genomic stability, development, and aging. Standard laboratory approaches range from basic molecular genetics, biochemistry, cytogenetics, and genomics to gene-targeted mutation and the generation of novel animal-based approaches and models.

Recent Graduate Student Rotation Projects.
1. Analysis of the SIRT1 or SIRT6 Proteins to elucidate catalytic activities and potential downstream targets (two projects).
2. Gene targeted inactivation of S regions to study the mechanism of IgH class switch recombination.
3. Generation of a recombinational cassette to study the mechanism by which TCRa and TCRd rearrangements are controlled.
4. Genetic and biochemical elucidation of posttranslational AID modifications and interacting proteins.
5. Cytogenetic analyses of the role of DNA DSB response or DNA end-joining proteins on maintenance of genomic stability (two separate rotation projects).

 

References:

  • Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Rangananth, S., Li, G., Schrum, J.P., Manis, J.P. and Alt, F.W. (2005) The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature, 438, 508-511.
  • Mostoslavsky, R., et al. (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124, 315-329.
  • Franco, S. Gostissa, M., Zha, S., Lombard, D.B., Murphy, M.M., Zarrin, A.A., Yan, C., Tepsuporn, S., Morales, J.C., Adams, M.M., Lou, Z., Bassing, C.H., Manis, J.P., Chen, J., Carpenter. P.B., and Alt, F.W. (2006) H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Molecular Cell, 21, 201-214.
  • Zarrin, A.A., Del Vecchio, C., Tseng, E., Gleason, M., Tian, M., and Alt, F.W. (2007) Antibody Class Switching Mediated by Yeast Endonuclease Generated DNA Breaks. Science 315, 377-381.