Immunology
 DMS Home  /  About DMS  /  Current Student Resources  /  Contact Us  /  Search 

Frederick W. Alt

Department of Genetics and Pediatrics
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
15 postdoctoral fellows, 3 graduate students

 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.

 

Papers & Publications

  1. Jung, D., Bassing, C.H., Fugmann, S.D., Cheng, H-L., Schatz, D.G., and Alt, F.W. (2003) Extrachromosomal recombination substrates recapitulate beyond 12/23 restricted V(D)J recombination in non-lymphoid cells. Immunity 18, 65-74.
  2. Wu, C., Bassing, C.H., Jung, D., Woodman, B.B., Foy, D., and Alt , F.W. (2003) Dramatically increased rearrangement and peripheral represent of V?14 driven by the 3’D???recombination signal sequence. Immunity 18, 75-85.
  3. Shinkura, R., Tian, M., Smith, M., Chua, K., Fujiwara, Y., and Alt., F.W. (2003) The influence of transcriptional orientation on endogenous switch region function. Nature Immunology 4, 435-441.
  4. Chaudhuri, J., Tian, M., Khuong, C., Chua, K., Pinaud, E., and Alt, F.W. (2003) Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726-730.
  5. Bassing, C.H, Suh, H., Ferguson, D.O. Chua, K.F., Manis, J., Eckersdorff, M., Gleason, M. Bronson R., Lee, C. and Alt, F.W. (2003) Histone H2AX: A dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359-370.
  6. Dudley, D.D., Sekiguchi, J., Sadofsky, M.J., Whitlow, S., DeVido, J., Monroe, R.J., Bassing, C.H., and Alt, F. (2003) Impaired V(D)J recombination and lymphocyte development in RAG1-expressing mice. J. Exp. Med. 198, 1439-1450.
  7. Chaudhuri, J., Khoung, C. and Alt, F.W. (2004) Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430, 992-998.
  8. Zarrin, A.A., Alt, F.W., Chaudhuri, J., Stokes, N., Kaushal, D., Du Pasquier, L. and Tian, M. (2004) An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nature Immunology 5, 1275-1281.
  9. Rooney, S., Alt, F.W., Sekiguchi, J. and Manis, J.P. (2005) Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc. Natl. Acad. Sci. 102, 2471-2475.
  10. Lombard, D.B., Chua, K.F., Mostoslavsky, R., Franco, S., Gostissa, M., and Alt, F.W. 2005) DNA repair, genomic stability, and aging. Cell 120, 497-512.
  11. Chua, K.F., Mostoslavsky, R., Lombard, D.B., Pang, W.W., Saito, S., Franco, S., Kaushal, D., Cheng, H.-L., Fischer, M.R., Stokes, N., Murphy, M.M., Appella, E., and Alt, F.W. (2005) Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metabolism, 2, 67-76.
  12. Perlot, T., Alt, F.W., Bassing, C.H., Suh, H. and Pinaud, E. (2005) Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc. Natl. Acad. Sci. USA, 102, 14362-14367.
  13. 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 enzme is regulated by protein kinase A phosphorylation. Nature, 438, 508-511.
  14. 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.
  15. Mostoslavsky, R., Chua, K.F., Lombard, D.B., Pang, W.W., Fischer, M.R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M.M., Mills, K.D., Patel, P., Hsu, J.T., Hong, A.L., Fore, E., Cheng, H.-L., Kennedy, C., Nunez, N., Bronson, R., Frendewey, D., Auerbach, W., Valenzuela, D., Karow, M., Hottiger, M.O., Hursting, S., Barrett, J.C., Guarente, L., Mulligan, R., Demple, B., Yancopoulos, G.D., and Alt, F.W. (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124, 315-329.