Frederick W. Alt

Department of Genetics
HHMI/Children's Hospital/Immune Disease 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
11 postdoctoral fellows, 3 graduate students, 2 visiting professors

The broad focus of the Alt lab is the elucidation of mechanisms that maintain genomic stability in mammalian cells. More specifically, the lab studies V(D)J recombination in developing B and T lymphocytes and the IgH heavy chain class switch recombination (CSR) and somatic hypermutation in mature B lymphocytes. Studies of these processes employ biochemical approaches to elucidate molecular mechanisms by which the RAG endonuclease and Activation Induced Cytidine Deaminase function on DNA to initiate, respectively, VDJ recombination and CSR. Other studies focus on the elucidation of genetic and epigenetic chromosomal processes that regulate how RAG and AID are targeted to their specific chromosomal DNA substrates. Other studies employ genetic and cytogenetic approaches to study roles of general DNA double strand break (DSB) repair and response pathways in VDJ recombination and CSR, andthe interplay of DSB repair and response pathways in suppressing genomic instability and cancer. For such studies, the lab developed several new models for B and T cell lymphomas and brain tumors. A major new lab research area focuses on how organization of the genome in the nucleus influences programmed gene rearrangments and chromosomal translocations. For this purpose, they have developed a high throughput genomic translocation sequencing strategy to identify the universe of translocations that arise from a fixed DSB. They are using this approach to generate a map of translocation partners for specific DSBs (e.g. a translocatome) with the goal of establishing basic mechnanistic principles that govern translocations in mouse and human cells.

Recent Graduate Student Rotation Projects.

1. Genetic and cytogenetic studies of the function of the IgH 3' regulatory region in promoting oncogenic translocatons with the c-myc gene.

2. Genetic and biochemical elucidation of posttranslational AID modifications and interacting proteins.

3. Analyses of the role of alternative end-joining pathways in IgH class switching and chromsomal translocations.

References:

Wang, J.H., Gostissa, M., Yan, C.T., Goff, P., Hickernell, T., Hansen, E., Difilippantonio, S., Wesemann, D.R., Zarrin, A.A., Rajewsky, K., Nussenzweig, A. and Alt, F.W. (2009) Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 460, 231-236
Gostissa, M., Yan, C.T., Bianco, J.M., Cogné, M., Pinaud, E. and Alt, F.W. (2009) Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature 462, 803-807. PMC2802177
Boboila, C., Yan, C., Wesemann, D.R., Jankovic, M., Wang, J.H., Manis, J., Nussenzweig, A., Nussenzweig, M. and Alt, F.W. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J. Ex. Med. 207, 417-427. PMC2822597
Boboilia, C., Jankovic, M., Yan, C.T., Wang, J.H., Wesemann, D.R., Zhang, T., Fazeli, A., Feldman, L., Nussenzweig, A., Nussenzweig, M. and Alt, F.W. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc. Natl. Acad. Sci. USA. 107, 3034-3039. PMC2840344
Zhang, T., Franklin, A., Boboila, C., McQuay, A., Gallagher, M.P., Manis, J.P., Khamlihi, A.A. and Alt, F.W. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM swithch regions. Proc. Natl. Acad. Sci. USA. 107, 3040-3045. PMC2840363

For a complete listing of publications on PubMed, click here.

BBS webpage updated 5/15/2010