A hypermutable insert in an immunoglobulin transgene contains hotspots of somatic mutation and sequences predicting highly stable structures in the RNA transcript

Journal of Experimental Medicine

Volumn 188, Issue 4, 1998, Pages 689-698

  Storb, Ursula ^a   Klotz, Emily L ^a,b   Hackett Jr , John ^a,c   Kage, Karen ^a   Bozek, Grazyna ^a   Martin, Terence E ^a  

^a UNIVERSITY OF CHICAGO   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

^c ABBOTT LABORATORIES   (United States)

Author keywords

Hot spots; Ig genes; RNA polymerase pausing; RNA secondary structure; Somatic hypermutation

Indexed keywords

ANTIGEN; DNA; IMMUNOGLOBULIN; NUCLEOTIDE; RESTRICTION ENDONUCLEASE; RNA; RNA POLYMERASE;

ANIMAL CELL; ARTICLE; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; POLYMERASE CHAIN REACTION; PREDICTION; PRIORITY JOURNAL; SOMATIC MUTATION; TRANSCRIPTION INITIATION; TRANSGENE;

ANIMALS; BASE SEQUENCE; BINDING SITES; DEOXYRIBONUCLEASES, TYPE II SITE-SPECIFIC; DNA, COMPLEMENTARY; IMMUNOGLOBULIN JOINING REGION; IMMUNOGLOBULIN KAPPA-CHAINS; IMMUNOGLOBULIN VARIABLE REGION; MICE; MICE, TRANSGENIC; MOLECULAR SEQUENCE DATA; MUTAGENESIS, INSERTIONAL; NUCLEIC ACID CONFORMATION; RNA; TRANSGENES;

EID: 0032541394     PISSN: 00221007     EISSN: None     Source Type: Journal    
DOI: 10.1084/jem.188.4.689     Document Type: Article

References (30)

1. Kelsoe, G. 1995. The germinal center reaction. Immunol. Today. 16:324-326.
2. MacLennan, I. 1994. Germinal centers. Annu. Rev. Immunol. 112:117-139.
3. Storb, U. 1996. The molecular basis of somatic hypermutation of immunoglobulin genes. Curr. Opin. Immunol. 8:206-214.
4. Hackett, J., B. Rogerson, R. O'Brien, and U. Storb. 1990. Analysis of somatic mutations in κ transgenes. J. Exp. Med. 172:131-137.
5. Betz, A., C. Milstein, R. Gonzalez-Fernandes, R. Pannell, T. Larson, and M. Neuberger. 1994. Elements regulating somatic hypermutation of an immunoglobulin κ gene: critical role for the intron enhancer/matrix attachment region. Cell. 77:239-248.
6. Tumas-Brundage, K., and T. Manser. 1997. The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J. Exp. Med. 185:239-250.
7. Peters, A., and U. Storb. 1996. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity. 4:57-65.
8. Storb, U., A. Peters, E. Klotz, N. Kim, H.M. Shen, K. Kage, and U. Rogerson. 1998. Somatic hypermutation of immunoglobulin genes is linked to transcription. Curr. Topics Microbiol. Immunol. 229:11-19.
9. Wagner, S., J. Elvin, P. Norris, J. McGregor, and M. Neuberger. 1996. Somatic hypermutation of Ig genes in patients with xeroderma pigmentosum (XP-D). Int. Immunol. 8: 701-705.
10. Shen, H.M., D.L. Cheo, E. Friedberg, and U. Storb. 1997. The inactivation of the XP-C gene does not affect somatic hypermutation or class switch recombination of immunoglobulin genes. Mol. Immunol. 34:527-533.
11. Kim, N., K. Kage, F. Matsuda, M.-P. Lefranc, and U. Storb. 1997. B lymphocytes of xeroderma pigmentosum or Cockayne syndrome patients with inherited defects in nucleotide excision repair are fully capable of somatic hypermutation of immunoglobulin genes. J. Exp. Med. 186:413-419.
12. Jacobs, H., Y. Fukita, G. van der Horst, J. de Boer, G. Weeda, J. Essers, N. de Wind, B. Engelward, L. Samson, S. Verbeek, et al. 1998. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice. J. Exp. Med. 187:1735-1743.
13. Phung Q., D. Winter, A. Cranston, R. Tarone, W. Bohr, R. Fishel, and P. Gearhart. 1998. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient for the MSH2 mismatch repair protein. J. Exp. Med. 187:1745-1751.
14. Winter, D., Q. Phung, A. Umar, S. Baker, R. Tarone, R. Tanaka, R. Liskay, T. Kunkel, V. Bohr, and P. Gearhart. 1998. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. Proc. Natl. Acad. Sci. USA. 95:6953-6958.
15. Kim, N., and U. Storb. 1998. The role of DNA repair in somatic hypermutation of immunoglobulin genes. J. Exp. Med. 187:1729-1733.
16. Klotz, E., J.J. Hackett, and U. Storb. 1998. Somatic hypermutation of an artificial test substrate within an Ig kappa transgene. J. Immunol. 161:782-790.
17. Smith, D., G. Creadon, P. Jena, J. Portanova, B. Kotzin, and L. Wysocki. 1996. Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells. J. Immunol. 156:2642-2652.
18. Govenchea, B., and C. Milstein. 1996. Modifying the sequence of an Immunoglobulin V-gene alters the resulting pattern of hypermutation. Proc. Natl. Acad. Sci. USA. 93: 13979-13984.
19. Doerner, T., H.-P. Brezinschek, R. Brezinschek, S. Foster, R. Domiati-Saad, and P. Lipsky. 1997. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J. Immunol. 138:2779-2789.
20. Rogozin, I., and N. Kolchanov. 1992. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighboring base sequences on mutagenesis. Biochim. Biophys. Acta. 1171:11-18.
21. Zucker, M. 1989. On finding all suboptimal folding of an RNA molecule. Science. 244:48-52.
22. Golding, G., P. Gearhart, and B. Glockman. 1987. Patterns of somatic mutation in immunoglobulin variable genes. Genetics. 115:169-176.
23. Shen, H., A. Peters, B. Baron, X. Zhu, and U. Storb. 1998. Mutation of the BCL6 gene in normal B cells by the process of somatic hypermutation of immunoglobulin genes. Science. 280:1750-1752.
24. Harrington, J., and M. Lieber. 1994. The characterization of a mammalian DNA structure-specific endonuclease. EMBO (Eur. Mol. Biol. Organ.) J. 13:1235-1246.
25. Klungland, A., and T. Lindahl. 1997. Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO (Eur. Mol. Biol. Organ.) J. 16:3341-3348.
26. Uptain, S., C. Kane, and M. Chamberlin. 1997. Basic mechanisms of transcript elongation and its regulation. Annu. Rev. Biochem. 66:117-172.
27. Nudler, E., A. Mustaev, E. Lukhtanov, and A. Goldfarb. 1997. The RNA-DNA hybrid maintains the register of transcription by preventing backtracking of RNA polymerase. Cell. 89:33-41.
28. Kane, C.M. 1994. Transcript elongation and gene regulation in eukaryotes. In Transcription: Mechanisms and Regulation. R.C. Conaway and J.W. Conaway, editor. Raven Press, Ltd., New York, NY. 279-296.
29. Reines, D. 1994. Nascent RNA cleavage by transcription elongation complexes. In Transcription: Mechanisms and Regulation. R.C. Conaway and J.W. Conaway, editor. Raven Press, Ltd., New York, NY. 263-278.
30. McCracken, S., N. Fong, K. Yankulov, S. Ballantyne, G. Pan, J. Greenblatt, S. Patterson, M. Wickens, and D. Bentley. 1997. The COOH-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature. 385: 357-361.