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Identification and functional analysis of novel BRCA1 transcripts, including mouse Brca1-Iris and human pseudo-BRCA1

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Abstract

Recent characterization of the mammalian transcriptome has confirmed its predicted complexity, with many loci encoding multiple splice variants and pseudogenes. The breast cancer susceptibility gene BRCA1 is a tumour suppressor gene that produces multiple functional transcripts. For example, BRCA1-IRIS is a splice variant of BRCA1, which encodes a protein that is functionally distinct from BRCA1. Here we describe the identification of ten novel Brca1 splice variants including Brca1-Iris, the mouse orthologue of human BRCA1-IRIS. We show that Brca1-Iris is differentially expressed during mammary epithelial differentiation and regulates survival of mammary epithelial cells. Another transcript, Brca1-Δ22, expressed in both mouse and human cells, was found to be defective in transcriptional activation capacity. Finally, we show that the human BRCA1 pseudogene produces a spliced pseudoBRCA1 transcript. The identification of these transcripts has implications for the understanding of the role of BRCA1 in biology and disease and for the interpretation of mouse knockout models.

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References

  1. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C et al (2005) The transcriptional landscape of the mammalian genome. Science 309(5740):1559–1563. doi:10.1126/science.1112014

    Article  CAS  PubMed  Google Scholar 

  2. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336. doi:10.1146/annurev.biochem.72.121801.161720

    Article  CAS  PubMed  Google Scholar 

  3. Caceres JF, Kornblihtt AR (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet 18(4):186–193. doi:10.1016/S0168-9525(01)02626-9

    Article  CAS  PubMed  Google Scholar 

  4. Pettigrew CA, Brown MA (2008) Pre-mRNA splicing aberrations and cancer. Front Biosci 13:1090–1105. doi:10.2741/2747

    Article  CAS  PubMed  Google Scholar 

  5. Yano Y, Saito R, Yoshida N, Yoshiki A, Wynshaw-Boris A, Tomita M, Hirotsune S (2004) A new role for expressed pseudogenes as ncRNA: regulation of mRNA stability of its homologous coding gene. J Mol Med 82(7):414–422. doi:10.1007/s00109-004-0550-3

    Article  CAS  PubMed  Google Scholar 

  6. Rosen EM, Fan S, Pestell RG, Goldberg ID (2003) BRCA1 gene in breast cancer. J Cell Physiol 196(1):19–41. doi:10.1136/mp.56.4.191

    Article  CAS  PubMed  Google Scholar 

  7. Orban TI, Olah E (2003) Emerging roles of BRCA1 alternative splicing. Mol Pathol 56(4):191–197. doi:10.1136/mp.56.4.191

    Article  CAS  PubMed  Google Scholar 

  8. Mixon M, Kittrell F, Medina D (2000) Expression of Brca1 and splice variant Brca1delta11 RNA levels in mouse mammary gland during normal development and tumourigenesis. Oncogene 19(46):5237–5243. doi:10.1038/sj.onc.1203905

    Article  CAS  PubMed  Google Scholar 

  9. ElShamy WM, Livingston DM (2004) Identification of BRCA1-IRIS, a BRCA1 locus product. Nat Cell Biol 6(10):954–967. doi:10.1038/ncb1171

    Article  CAS  PubMed  Google Scholar 

  10. Nakuci E, Mahner S, Direnzo J, ElShamy WM (2006) BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells. Exp Cell Res 312(16):3120–3131. doi:10.1016/j.yexcr.2006.06.021

    Article  CAS  PubMed  Google Scholar 

  11. Abel KJ, Xu J, Yin GY, Lyons RH, Meisler MH, Weber BL (1995) Mouse Brca1: localization sequence analysis and identification of evolutionarily conserved domains. Hum Mol Genet 4(12):2265–2273. doi:10.1093/hmg/4.12.2265

    Article  CAS  PubMed  Google Scholar 

  12. Sharan SK, Wims M, Bradley A (1995) Murine Brca1: sequence and significance for human missense mutations. Hum Mol Genet 4(12):2275–2278. doi:10.1093/hmg/4.12.2275

    Article  CAS  PubMed  Google Scholar 

  13. Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, Wakeham A, Potter J, Reitmair A, Billia F et al (1996) The tumour suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85(7):1009–1023. doi:10.1016/S0092-8674(00)81302-1

    Article  CAS  PubMed  Google Scholar 

  14. Dimitrov S, Brennerova M, Forejt J (2001) Expression profiles and intergenic structure of head-to-head oriented Brca1 and Nbr1 genes. Gene 262(1–2):89–98. doi:10.1016/S0378-1119(00)00549-7

    Article  CAS  PubMed  Google Scholar 

  15. Mendell JT, Dietz HC (2001) When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell 107(4):411–414. doi:10.1016/S0092-8674(01)00583-9

    Article  CAS  PubMed  Google Scholar 

  16. Debnath J, Muthuswamy SK, Brugge JS (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30(3):256–268. doi:10.1016/S1046-2023(03)00032-X

    Article  CAS  PubMed  Google Scholar 

  17. Naylor MJ, Oakes SR, Gardiner-Garden M, Harris J, Blazek K, Ho TW, Li FC, Wynick D, Walker AM, Ormandy CJ (2005) Transcriptional changes underlying the secretory activation phase of mammary gland development. Mol Endocrinol 19(7):1868–1883. doi:10.1210/me.2004-0254

    Article  CAS  PubMed  Google Scholar 

  18. Sum EY, Peng B, Yu X, Chen J, Byrne J, Lindeman GJ, Visvader JE (2002) The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumour suppressor BRCA1 and inhibits BRCA1 activity. J Biol Chem 277(10):7849–7856. doi:10.1074/jbc.M110603200

    Article  CAS  PubMed  Google Scholar 

  19. Xu CF, Chambers JA, Solomon E (1997) Complex regulation of the BRCA1 gene. J Biol Chem 272(34):20994–20997. doi:10.1074/jbc.272.34.20994

    Article  CAS  PubMed  Google Scholar 

  20. Saunus JM, Edwards SL, French JD, Smart CE, Brown MA (2007) Regulation of BRCA1 messenger RNA stability in human epithelial cell lines and during cell cycle progression. FEBS Lett 581(18):3435–3442. doi:10.1016/j.febslet.2007.06.046

    Article  CAS  PubMed  Google Scholar 

  21. Pear WS, Nolan GP, Scott ML, Baltimore D (1993) Production of high-titre helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA 90(18):8392–8396. doi:10.1073/pnas.90.18.8392

    Article  CAS  PubMed  Google Scholar 

  22. Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN (1999) The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter. Oncogene 18(1):263–268. doi:10.1038/sj.onc.1202323

    Article  CAS  PubMed  Google Scholar 

  23. Brown MA, Xu CF, Nicolai H, Griffiths B, Chambers JA, Black D, Solomon E (1996) The 5′ end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21. Oncogene 12(12):2507–2513

    CAS  PubMed  Google Scholar 

  24. Evers B, Jonkers J (2006) Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25(43):5885–5897. doi:10.1038/sj.onc.1209871

    Article  CAS  PubMed  Google Scholar 

  25. Hohenstein P, Kielman MF, Breukel C, Bennett LM, Wiseman R, Krimpenfort P, Cornelisse C, van Ommen GJ, Devilee P, Fodde R (2001) A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage. Oncogene 20(20):2544–2550. doi:10.1038/sj.onc.1204363

    Article  CAS  PubMed  Google Scholar 

  26. Anderson SF, Schlegel BP, Nakajima T, Wolpin ES, Parvin JD (1998) BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet 19(3):254–256. doi:10.1038/930

    Article  CAS  PubMed  Google Scholar 

  27. Au WW, Henderson BR (2005) The BRCA1 RING and BRCT domains cooperate in targeting BRCA1 to ionizing radiation-induced nuclear foci. J Biol Chem 280(8):6993–7001. doi:10.1074/jbc.M408879200

    Article  CAS  PubMed  Google Scholar 

  28. Lovelock PK, Healey S, Au W, Sum EY, Tesoriero A, Wong EM, Hinson S, Brinkworth R, Bekessy A, Diez O et al (2006) Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants. J Med Genet 43(1):74–83. doi:10.1136/jmg.2005.033258

    Article  CAS  PubMed  Google Scholar 

  29. Lovelock PK, Spurdle AB, Mok MT, Farrugia DJ, Lakhani SR, Healey S, Arnold S, Buchanan D, Couch FJ, Henderson BR et al (2007) Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res 9(6):R82. doi:10.1186/bcr1826

    Article  PubMed  Google Scholar 

  30. Kozak M (1986) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44(2):283–292. doi:10.1016/0092-8674(86)90762-2

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Bob Simpson from The University of Queensland for real-time PCR technical assistance and Dr. Gordon Peters for pBABE vectors and BOSC-23 cells. MCF7s expressing the murine ecotropic receptor were kindly provided by Dr. Andrew Deans and HC11 cells were kindly provided by Dr. Chris Ormandy (with permission from N. Hynes). This work was supported by funds from the National Health and Medical Research Council (401651 and 143037) and the University of Queensland. J. French was supported by a National Breast Cancer Foundation Training Fellowship and A. Sauer was supported by a German Academic Exchange Service (DAAD).

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Authors and Affiliations

  1. School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, QLD, 4072, Australia

    Christopher A. Pettigrew, Juliet D. French, Jodi M. Saunus, Stacey L. Edwards, Aisha V. Sauer, Chanel E. Smart, Therese Lundström, Christiane Wiesner, Joseph A. Rothnagel & Melissa A. Brown

  2. Queensland Institute of Medical Research, Herston, QLD, 4006, Australia

    Amanda B. Spurdle

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  1. Christopher A. Pettigrew
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  2. Juliet D. French
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  3. Jodi M. Saunus
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Correspondence to Melissa A. Brown.

Additional information

Christopher A. Pettigrew, Juliet D. French, and Jodi M. Saunus contributed equally to the work.

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Pettigrew, C.A., French, J.D., Saunus, J.M. et al. Identification and functional analysis of novel BRCA1 transcripts, including mouse Brca1-Iris and human pseudo-BRCA1 . Breast Cancer Res Treat 119, 239–247 (2010). https://doi.org/10.1007/s10549-008-0256-2

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