Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2

Nature Structural & Molecular Biology volume 17, pages 1255–1259 (2010)Cite this article

Subjects

Abstract

Homologous recombination mediated by RAD51 recombinase helps eliminate chromosomal lesions, such as DNA double-strand breaks induced by radiation or arising from injured DNA replication forks. The tumor suppressors BRCA2 and PALB2 act together to deliver RAD51 to chromosomal lesions to initiate repair. Here we document a new function of PALB2: to enhance RAD51's ability to form the D loop. We show that PALB2 binds DNA and physically interacts with RAD51. Notably, although PALB2 alone stimulates D-loop formation, it has a cooperative effect with RAD51AP1, an enhancer of RAD51. This stimulation stems from the ability of PALB2 to function with RAD51 and RAD51AP1 to assemble the synaptic complex. Our results demonstrate the multifaceted role of PALB2 in chromosome damage repair. Because PALB2 mutations can cause cancer or Fanconi anemia, our findings shed light on the mechanism of tumor suppression in humans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PALB2 purification.
Figure 2: DNA binding by PALB2.
Figure 3: PALB2 and RAD51AP1 enhance the RAD51-mediated D-loop reaction.
Figure 4: Effect of PALB2 on formation of DNA damage–induced RAD51AP1 foci.
Figure 5: PALB2 enhances synaptic complex assembly.

Similar content being viewed by others

References

  1. San Filippo, J., Sung, P. & Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008).

    Article  CAS  Google Scholar 

  2. Moynahan, M.E., Pierce, A.J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).

    Article  CAS  Google Scholar 

  3. San Filippo, J. et al. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J. Biol. Chem. 281, 11649–11657 (2006).

    Article  CAS  Google Scholar 

  4. Tutt, A. et al. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9, 1107–1110 (1999).

    Article  CAS  Google Scholar 

  5. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    Article  CAS  Google Scholar 

  6. Yu, V.P. et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14, 1400–1406 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Erkko, H. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).

    Article  CAS  Google Scholar 

  8. Foulkes, W.D. et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 9, R83 (2007).

    Article  Google Scholar 

  9. Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).

    Article  CAS  Google Scholar 

  10. Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

    Article  CAS  Google Scholar 

  11. Hirsch, B. et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 103, 2554–2559 (2004).

    Article  CAS  Google Scholar 

  12. Sy, S.M., Huen, M.S. & Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl. Acad. Sci. USA 106, 7155–7160 (2009).

    Article  CAS  Google Scholar 

  13. Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).

    Article  CAS  Google Scholar 

  14. Modesti, M. et al. RAD51AP1 is a structure-specific DNA binding protein that stimulates joint molecule formation during RAD51-mediated homologous recombination. Mol. Cell 28, 468–481 (2007).

    Article  CAS  Google Scholar 

  15. Wiese, C. et al. Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement. Mol. Cell 28, 482–490 (2007).

    Article  CAS  Google Scholar 

  16. Sung, P., Krejci, L., Van Komen, S. & Sehorn, M.G. Rad51 recombinase and recombination mediators. J. Biol. Chem. 278, 42729–42732 (2003).

    Article  CAS  Google Scholar 

  17. Gupta, R.C., Folta-Stogniew, E., O'Malley, S., Takahashi, M. & Radding, C.M. Rapid exchange of A:T base pairs is essential for recognition of DNA homology by human Rad51 recombination protein. Mol. Cell 4, 705–714 (1999).

    Article  CAS  Google Scholar 

  18. Chi, P., San Filippo, J., Sehorn, M.G., Petukhova, G.V. & Sung, P. Bipartite stimulatory action of the Hop2–Mnd1 complex on the Rad51 recombinase. Genes Dev. 21, 1747–1757 (2007).

    Article  CAS  Google Scholar 

  19. Pezza, R.J., Voloshin, O.N., Vanevski, F. & Camerini-Otero, R.D. Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing. Genes Dev. 21, 1758–1766 (2007).

    Article  CAS  Google Scholar 

  20. Yang, H., Li, Q., Fan, J., Holloman, W.K. & Pavletich, N.P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. Nature 433, 653–657 (2005).

    Article  CAS  Google Scholar 

  21. Yuan, S.S. et al. BRCA2 is required for ionizing radiation–induced assembly of Rad51 complex in vivo. Cancer Res. 59, 3547–3551 (1999).

    CAS  PubMed  Google Scholar 

  22. Walsh, T. & King, M.C. Ten genes for inherited breast cancer. Cancer Cell 11, 103–105 (2007).

    Article  CAS  Google Scholar 

  23. Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat. Genet. 39, 159–161 (2007).

    Article  CAS  Google Scholar 

  24. Wiese, C. et al. Interactions involving the Rad51 paralogs Rad51C and XRCC3 in human cells. Nucleic Acids Res. 30, 1001–1008 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to R. Buisson and J.-Y. Masson (Centre de Recherche du Centre hospitalier universitaire de Québec) for the communication of results before publication, to S. Begovic, S. Longerich and Y.-C. Kim (Yale University) for assistance, to Y. Kwon (Yale University) for providing ScRad51 protein and to B. Xia (Department of Radiation Oncology, The Cancer Institute of NJ) for providing PALB2-deficient and PALB2-complemented cells, as well as for providing PALB2 antibody. This study was supported by research and program project grants RO1CA120315, RO1ES07061, RO1ES015252, RO1ES015632, PO1CA129186 and PO1CA92584 from the US National Institutes of Health and by postdoctoral fellowship PDF0706844 from the Susan G. Komen for the Cure Foundation.

Author information

Author notes

  1. Shirley M-H Sy & Junjie Chen

    Present address: Present addresses: Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong (S.M.-H.S.) and Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA (J.C.).,

  2. Eloïse Dray and Julia Etchin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA

    Eloïse Dray, Julia Etchin, Dorina Saro, Dongqing Liu & Patrick Sung

  2. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA

    Claudia Wiese, Gareth J Williams, Michal Hammel, Miaw-Sheue Tsai & David Schild

  3. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA

    Xiong Yu, Vitold E Galkin & Edward Egelman

  4. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Shirley M-H Sy & Junjie Chen

Authors
  1. Eloïse Dray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Etchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Wiese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dorina Saro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gareth J Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michal Hammel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vitold E Galkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dongqing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Miaw-Sheue Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shirley M-H Sy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David Schild
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Edward Egelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Junjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Patrick Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.D., J.E. and C.W. conceived and carried out experiments; E.D. and C.W. also wrote the paper. D. Saro, G.J.W., M.H., X.Y., V.E.G., C.W., D.L., M.-S.T. and S.M.-H.S. contributed key material. D. Schild, E.E., J.C. and P.S. contributed expertise. P.S. provided guidance throughout, wrote and edited the paper.

Corresponding authors

Correspondence to Eloïse Dray or Patrick Sung.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 3812 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dray, E., Etchin, J., Wiese, C. et al. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat Struct Mol Biol 17, 1255–1259 (2010). https://doi.org/10.1038/nsmb.1916

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1916

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing