Abstract

This application proposes the continuation of studies on somatic hypermutation of immunoglobulin (Ig) genes. During the previous funding period a connection between somatiC hypermutation and initiation of transcription was found, leading to a model of transcription coupled repair initiated by a specific mutator factor. Decisive experiments to test this model are proposed, most of them based on the use of transgenic mice carrying various test transgenes. These studies are important for the understanding of the creation of the varied repertoire of variable Ig genes with the potential of reaCting against any foreign antigenic determinant, including perhaps tumor cell antigens. Furthermore, somatic hypermutation has been implicated in autoimmune diseases. It is likely that understanding the components involved in somatic mutation will aid in understanding the genetic and environmental causes of autoimmunity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038649-11
Application #
2770948
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-07-01
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Michael, Nancy; Martin, Terence E; Nicolae, Dan et al. (2002) Effects of sequence and structure on the hypermutability of immunoglobulin genes. Immunity 16:123-34
Shen, H M; Peters, A; Kao, D et al. (2001) The 3' Igkappa enhancer contains RNA polymerase II promoters: implications for endogenous and transgenic kappa gene expression. Int Immunol 13:665-74
Storb, U; Shen, H M; Michael, N et al. (2001) Somatic hypermutation of immunoglobulin and non-immunoglobulin genes. Philos Trans R Soc Lond B Biol Sci 356:13-9
Shen, H M; Michael, N; Kim, N et al. (2000) The TATA binding protein, c-Myc and survivin genes are not somatically hypermutated, while Ig and BCL6 genes are hypermutated in human memory B cells. Int Immunol 12:1085-93
Storb, U; Peters, A; Kim, N et al. (1999) Molecular aspects of somatic hypermutation of immunoglobulin genes. Cold Spring Harb Symp Quant Biol 64:227-34
Kim, N; Bozek, G; Lo, J C et al. (1999) Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications. J Exp Med 190:21-30
Storb, U; Peters, A; Klotz, E et al. (1998) Cis-acting sequences that affect somatic hypermutation of Ig genes. Immunol Rev 162:153-60
Storb, U; Peters, A; Klotz, E et al. (1998) Immunoglobulin transgenes as targets for somatic hypermutation. Int J Dev Biol 42:977-82
Klotz, E L; Hackett Jr, J; Storb, U (1998) Somatic hypermutation of an artificial test substrate within an Ig kappa transgene. J Immunol 161:782-90
Kim, N; Storb, U (1998) The role of DNA repair in somatic hypermutation of immunoglobulin genes. J Exp Med 187:1729-33

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