Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Mar 29;91(7):2733–2737. doi: 10.1073/pnas.91.7.2733

Cell cycle regulation of V(D)J recombination-activating protein RAG-2.

W C Lin 1, S Desiderio 1
PMCID: PMC43444  PMID: 8146183

Abstract

The antigen receptors of B and T lymphocytes are encoded in multiple germ-line DNA segments that are joined during lymphocyte development. The recombination-activating proteins RAG-1 and RAG-2 are both essential for this process, termed V(D)J rearrangement. Phosphorylation of the RAG-2 protein at Thr-490 by one or more cyclin-dependent kinases is associated with its rapid degradation. In an immature B-cell line and in normal thymocytes, RAG-2 protein accumulates preferentially in the G0/G1 phases of the cell cycle and declines by at least 20-fold before cells enter S phase. The amount of RAG-2 protein remains low throughout the S, G2, and M phases. The amount of RAG-1 protein shows considerably less fluctuation. The variation in RAG-2 protein is likely to be established, at least in part, by a posttranscriptional mechanism. These observations suggest that V(D)J rearrangement occurs entirely or preferentially within G0/G1.

Full text

PDF
2733

Images in this article

2734Image
on p.2734
2734Image
on p.2734
2735Image
on p.2735
2736Image
on p.2736

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alessandrini A., Pierce J. H., Baltimore D., Desiderio S. V. Continuing rearrangement of immunoglobulin and T-cell receptor genes in a Ha-ras-transformed lymphoid progenitor cell line. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1799–1803. doi: 10.1073/pnas.84.7.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boyer P. D., Diamond R. A., Rothenberg E. V. Changes in inducibility of IL-2 receptor alpha-chain and T cell-receptor expression during thymocyte differentiation in the mouse. J Immunol. 1989 Jun 15;142(12):4121–4130. [PubMed] [Google Scholar]
  3. Feder J. N., Guidos C. J., Kusler B., Carswell C., Lewis D., Schimke R. T. A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation. J Cell Biol. 1990 Dec;111(6 Pt 1):2693–2701. doi: 10.1083/jcb.111.6.2693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Félix M. A., Labbé J. C., Dorée M., Hunt T., Karsenti E. Triggering of cyclin degradation in interphase extracts of amphibian eggs by cdc2 kinase. Nature. 1990 Jul 26;346(6282):379–382. doi: 10.1038/346379a0. [DOI] [PubMed] [Google Scholar]
  5. Herskowitz I. A regulatory hierarchy for cell specialization in yeast. Nature. 1989 Dec 14;342(6251):749–757. doi: 10.1038/342749a0. [DOI] [PubMed] [Google Scholar]
  6. Kastan M. B., Zhan Q., el-Deiry W. S., Carrier F., Jacks T., Walsh W. V., Plunkett B. S., Vogelstein B., Fornace A. J., Jr A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992 Nov 13;71(4):587–597. doi: 10.1016/0092-8674(92)90593-2. [DOI] [PubMed] [Google Scholar]
  7. Lewis S. M., Hesse J. E., Mizuuchi K., Gellert M. Novel strand exchanges in V(D)J recombination. Cell. 1988 Dec 23;55(6):1099–1107. doi: 10.1016/0092-8674(88)90254-1. [DOI] [PubMed] [Google Scholar]
  8. Lieber M. R., Hesse J. E., Mizuuchi K., Gellert M. Developmental stage specificity of the lymphoid V(D)J recombination activity. Genes Dev. 1987 Oct;1(8):751–761. doi: 10.1101/gad.1.8.751. [DOI] [PubMed] [Google Scholar]
  9. Lin W. C., Desiderio S. Regulation of V(D)J recombination activator protein RAG-2 by phosphorylation. Science. 1993 May 14;260(5110):953–959. doi: 10.1126/science.8493533. [DOI] [PubMed] [Google Scholar]
  10. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  11. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  12. Morzycka-Wroblewska E., Lee F. E., Desiderio S. V. Unusual immunoglobulin gene rearrangement leads to replacement of recombinational signal sequences. Science. 1988 Oct 14;242(4876):261–263. doi: 10.1126/science.3140378. [DOI] [PubMed] [Google Scholar]
  13. Nasmyth K. A repetitive DNA sequence that confers cell-cycle START (CDC28)-dependent transcription of the HO gene in yeast. Cell. 1985 Aug;42(1):225–235. doi: 10.1016/s0092-8674(85)80118-5. [DOI] [PubMed] [Google Scholar]
  14. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  15. Pergola F., Zdzienicka M. Z., Lieber M. R. V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol Cell Biol. 1993 Jun;13(6):3464–3471. doi: 10.1128/mcb.13.6.3464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Roth D. B., Menetski J. P., Nakajima P. B., Bosma M. J., Gellert M. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell. 1992 Sep 18;70(6):983–991. doi: 10.1016/0092-8674(92)90248-b. [DOI] [PubMed] [Google Scholar]
  17. Roth D. B., Nakajima P. B., Menetski J. P., Bosma M. J., Gellert M. V(D)J recombination in mouse thymocytes: double-strand breaks near T cell receptor delta rearrangement signals. Cell. 1992 Apr 3;69(1):41–53. doi: 10.1016/0092-8674(92)90117-u. [DOI] [PubMed] [Google Scholar]
  18. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  19. Schatz D. G., Oettinger M. A., Schlissel M. S. V(D)J recombination: molecular biology and regulation. Annu Rev Immunol. 1992;10:359–383. doi: 10.1146/annurev.iy.10.040192.002043. [DOI] [PubMed] [Google Scholar]
  20. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  21. Taccioli G. E., Rathbun G., Oltz E., Stamato T., Jeggo P. A., Alt F. W. Impairment of V(D)J recombination in double-strand break repair mutants. Science. 1993 Apr 9;260(5105):207–210. doi: 10.1126/science.8469973. [DOI] [PubMed] [Google Scholar]
  22. Yin Y., Tainsky M. A., Bischoff F. Z., Strong L. C., Wahl G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992 Sep 18;70(6):937–948. doi: 10.1016/0092-8674(92)90244-7. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES