Skip to main content

Advertisement

SpringerLink
Log in

Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

MERIT40 is a recently identified BRCA1 and RAP80 interacting protein that is essential for protein–protein interactions of a BRCA1 complex also containing Abraxas, BRCC36 and BRCC45. It is a mediator of checkpoint functions and DNA damage signaling through a (de)ubiquitination cascade. Based on its interaction with BRCA1 and its role in genome integrity maintenance, MERIT40 is a novel candidate gene for being involved in hereditary susceptibility to breast cancer. Here, we report to our knowledge the first comprehensive mutation screening of this gene in affected cases of breast cancer families. Only a number of sequence variants were found, four of which are novel. None of the observed variants appeared to be disease related, suggesting that germline mutations in MERIT40 are rare or absent in familial breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Anglian Breast Cancer Study Group (2000) Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83:1301–1308

    Article  Google Scholar 

  2. Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093

    Article  CAS  PubMed  Google Scholar 

  3. Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40:17–22

    Article  CAS  PubMed  Google Scholar 

  4. Rahman N, Stratton MR (1998) The genetics of breast cancer susceptibility. Annu Rev Genet 32:95–121

    Article  CAS  PubMed  Google Scholar 

  5. Wooster R, Weber BL (2003) Breast and ovarian cancer. N Engl J Med 348:2339–2347

    Article  CAS  PubMed  Google Scholar 

  6. Erkko H, Xia B, Nikkilä J et al (2007) A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316–319

    Article  CAS  PubMed  Google Scholar 

  7. Seal S, Thompson D, Renwick A et al (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38:1239–1241

    Article  CAS  PubMed  Google Scholar 

  8. Ghimenti C, Sensi E, Presciuttini S et al (2002) Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosom Cancer 33:235–242

    Article  CAS  PubMed  Google Scholar 

  9. Karppinen SM, Heikkinen K, Rapakko K et al (2004) Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J Med Genet 41:e114

    Article  PubMed  Google Scholar 

  10. Shao G, Patterson-Fortin J, Messick TE et al (2009) MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev 23:740–754

    Article  CAS  PubMed  Google Scholar 

  11. Feng L, Huang J, Chen J (2009) MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev 23:719–728

    Article  CAS  PubMed  Google Scholar 

  12. Wang B, Hurov K, Hofmann K et al (2009) NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev 23:729–739

    Article  CAS  PubMed  Google Scholar 

  13. Kim H, Chen J, Yu X (2007) Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316:1202–1205

    Article  CAS  PubMed  Google Scholar 

  14. Sobhian B, Shao G, Lilli DR et al (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316:1198–1202

    Article  CAS  PubMed  Google Scholar 

  15. Wang B, Matsuoka S, Ballif BA et al (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316:1194–1198

    Article  CAS  PubMed  Google Scholar 

  16. Ewing RM, Chu P, Elisma F et al (2007) Large-scale mapping of human protein–protein interactions by mass spectrometry. Mol Syst Biol 3:89

    Article  PubMed  Google Scholar 

  17. Rual JF, Venkatesan K, Hao T et al (2005) Towards a proteome-scale map of the human protein–protein interaction network. Nature 437:1173–1178

    Article  CAS  PubMed  Google Scholar 

  18. Kim H, Huang J, Chen J (2007) CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nat Struct Mol Biol 14:710–715

    Article  CAS  PubMed  Google Scholar 

  19. Liu Z, Wu J, Yu X (2007) CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol 14:716–720

    Article  CAS  PubMed  Google Scholar 

  20. Chen X, Arciero CA, Wang C et al (2006) BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation. Cancer Res 66:5039–5046

    Article  CAS  PubMed  Google Scholar 

  21. Dong Y, Hakimi MA, Chen X et al (2003) Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 12:1087–1099

    Article  CAS  PubMed  Google Scholar 

  22. Wang B, Elledge SJ (2007) Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 104:20759–20763

    Article  CAS  PubMed  Google Scholar 

  23. Shao G, Lilli DR, Patterson-Fortin J et al (2009) The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci USA 106:3166–3171

    Article  CAS  PubMed  Google Scholar 

  24. Stewart GS, Panier S, Townsend K et al (2009) The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136:420–434

    Article  CAS  PubMed  Google Scholar 

  25. Greenberg RA (2008) Recognition of DNA double strand breaks by the BRCA1 tumor suppressor network. Chromosoma 117:305–317

    Article  CAS  PubMed  Google Scholar 

  26. Nikkilä J, Coleman KA, Morrissey D et al (2009) Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function. Oncogene 28:1843–1852

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr. Aki Mustonen, Dr. Jaakko Ignatius and nurses Kari Mononen and Outi Kajula for their help in sample and data collection and also in patient contacts, Helmi Konola and Meeri Elina Otsukka for technical assistance and Hannele Erkko for critical reading of the manuscript. We thank all the patients and their family members for volunteering to participate in these studies, as well as the Finnish Red Cross Blood Service for help with collection of population control blood samples. This study was financially supported by the Sigrid Jusélius Foundation, the Academy of Finland, CIMO, the Orion-Farmos Research Foundation, the Northern Ostrobothnia Fund of the Finnish Cultural Foundation, the University of Oulu, and the Oulu University Hospital.

Author information

Authors and Affiliations

  1. Laboratory of Cancer Genetics, Department of Clinical Genetics and Biocenter Oulu, University of Oulu, Oulu University Hospital, P.O. Box 5000, 90014, Oulu, Finland

    Szilvia Solyom, Katri Pylkäs & Robert Winqvist

  2. Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA, 19104-6160, USA

    Jeffery Patterson-Fortin & Roger A. Greenberg

  3. Department of Pathology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA, 19104-6160, USA

    Roger A. Greenberg

  4. University of Pennsylvania School of Veterinary Medicine, 3800 Spruce St, Philadelphia, PA, 19104-6160, USA

    Jeffery Patterson-Fortin

Authors
  1. Szilvia Solyom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffery Patterson-Fortin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katri Pylkäs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger A. Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Winqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Winqvist.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 34 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solyom, S., Patterson-Fortin, J., Pylkäs, K. et al. Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families. Breast Cancer Res Treat 120, 165–168 (2010). https://doi.org/10.1007/s10549-009-0453-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0453-7

Keywords

Search

Navigation