BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A

Nature Genetics volume 19, pages254–256(1998)Cite this article

Abstract

The breast cancer specific tumour suppressor protein, BRCA1 (refs 1,2), activates transcription when linked with a DNA-binding domain3,4 and is a component of the RNA polymerase II (Pol II) holoenzyme5,6. We show here that RNA helicase A (RHA) protein7,8 links BRCA1 to the holoenzyme complex. The region of BRCA1 which interacts with RHA and, thus, the holoenzyme complex, corresponds to subregions of the BRCT domain of BRCA1 ( ref. 9). This interaction was shown to occur in yeast nuclei, and expression in human cells of a truncated RHA molecule which retains binding to BRCA1 inhibited transcriptional activation mediated by the BRCA1 carboxy terminus. These data are the first to identify a specific protein interaction with the BRCA1 C-terminal domain and are consistent with the model that BRCA1 functions as a transcriptional coactivator.

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Figure 1: RHA binds the C-terminal domain of BRCA1 in vitro.
Figure 2: BRCA1 interaction with RHA in vitro.
Figure 3: Transcription activation by GBD-BRCA1 C-terminus is inhibited by truncated RHA protein.

References

  1. 1

    Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 . Science 266, 66–71 (1994).

    CAS  Article  Google Scholar 

  2. 2

    Futreal, P.A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122 ( 1994).

    CAS  Article  Google Scholar 

  3. 3

    Monteiro, A.N., August, A. & Hanafusa, H. Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc. Natl Acad. Sci. USA 93, 13595–13599 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Chapman, M.S. & Verma, I.M. Transcriptional activation by BRCA1 . Nature 382, 678–679 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Scully, R. et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc. Natl Acad. Sci. U.S.A. 94, 5605–5610 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Neish, A.S., Anderson, S.F., Schlegel, B.P., Wei, W. & Parvin, J.D. Factors associated with the mammalian RNA polymerase II holoenzyme. Nucleic Acids Res. 26, 847– 853 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Lee, C.G. & Hurwitz, J. Human RNA helicase A is homologous to the maleless protein of Drosophila. J. Biol. Chem. 268, 16822–16830 (1993).

    CAS  Google Scholar 

  8. 8

    Zhang, S. & Grosse, F. Domain structure of human nuclear DNA helicase II (RNA helicase A). J. Biol. Chem. 272 , 11487–11494 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Koonin, E.V., Altschul, S.F. & Bork, P. BRCA1 protein products...Functional motifs. Nature Genet. 13, 266–268 (1996).

    CAS  Article  Google Scholar 

  10. 10

    Nakajima, T., Uchida, C., Anderson, S.F., Parvin, J.D. & Montminy, M. Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. Genes Dev. 11, 738–747 ( 1997).

    CAS  Article  Google Scholar 

  11. 11

    Bone, J.R. et al. Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. Genes Dev. 8, 96– 104 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Nakajima, T. et al. RNA helicase A mediates association of CBP with RNA polymerase II. Cell 90, 1107–1112 ( 1997).

    CAS  Article  Google Scholar 

  13. 13

    Szabo, C.I. & King, M.C. Inherited breast and ovarian cancer . Hum. Mol. Genet. 4, 1811– 1817 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Aspenstrom, P. & Olson, M.F. Yeast two-hybrid system to detect protein-protein interactions with Rho GTPases. Methods Enzymol. 256, 228–241 ( 1995).

    CAS  Article  Google Scholar 

  15. 15

    Somasundaram, K. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389, 187– 190 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Ouchi, T., Monteiro, A.N.A., August, A., Aaronson, S.A. & Hanafusa, H. BRCA1 regulates p53-dependent gene expression. Proc. Natl Acad. Sci. USA 95, 2302– 2306 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Tassan, J.P., Jaquenoud, M., Leopold, P., Schultz, S.J. & Nigg, E.A. Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. Proc. Natl Acad. Sci. USA 92, 8871–8875 ( 1995).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank A. Monteiro and H. Hanafusa for the kind gift of GBD-BRCA1 constructs, and we thank M. Montminy, A. Dutta and D. Haile for helpful advice during the course of these experiments. This work was supported in part by NIH grant GM53504, a Junior Faculty Research Award from the American Cancer Society and also a Massachusetts Dept. of Public Health Breast Cancer Research Program grant to J.D.P. S.F.A. is supported by NRSA GM18829 from the NIH, and T.N. is supported by the Uehara Memorial Foundation and by the Otsuka Pharmaceutical Company.

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Author notes

  1. Toshihiro Nakajima: Institute of Applied Biochemistry, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki Japan 305-8572. S.F.A. & B.P.S. contributed equally to this study.

Affiliations

  1. Division of Molecular Oncology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, 02115, Massachusetts, USA

    Stephen F. Anderson, Brian P. Schlegel, Eric S. Wolpin & Jeffrey D. Parvin

  2. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Toshihiro Nakajima

Authors
  1. Stephen F. Anderson
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  2. Brian P. Schlegel
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  3. Toshihiro Nakajima
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  4. Eric S. Wolpin
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  5. Jeffrey D. Parvin
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Correspondence to Jeffrey D. Parvin.

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Anderson, S., Schlegel, B., Nakajima, T. et al. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet 19, 254–256 (1998). https://doi.org/10.1038/930

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