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Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to polη-dependent bypass

Oncogene volume 29, pages 2499–2508 (2010)Cite this article

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Abstract

BRCA1 and the DNA helicase FANCJ (also known as BACH1 or BRIP1) have common functions in breast cancer suppression and DNA repair. However, the functional significance of the direct interaction between BRCA1 and FANCJ remains unclear. Here, we have discovered that BRCA1 binding to FANCJ regulates DNA damage repair choice. Thus, when FANCJ binding to BRCA1 is ablated, the molecular mechanism chosen for the repair of damaged DNA is dramatically altered. Specifically, a FANCJ protein that cannot be phosphorylated at serine 990 or bind BRCA1 inhibits DNA repair via homologous recombination and promotes polη-dependent bypass. Furthermore, the polη-dependent bypass promoted by FANCJ requires the direct binding to the mismatch repair (MMR) protein, MLH1. Together, our findings implicate that in human cells BRCA1 binding to FANCJ is critical to regulate DNA repair choice and promote genomic stability. Moreover, unregulated FANCJ function could be associated with cancer and/or chemoresistance.

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References

  • Albertella MR, Green CM, Lehmann AR, O'Connor MJ . (2005). A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res 65: 9799–9806.

    Article  CAS  PubMed  Google Scholar 

  • Alt A, Lammens K, Chiocchini C, Lammens A, Pieck JC, Kuch D et al. (2007). Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science 318: 967–970.

    Article  CAS  PubMed  Google Scholar 

  • Barbour L, Xiao W . (2003). Regulation of alternative replication bypass pathways at stalled replication forks and its effects on genome stability: a yeast model. Mutat Res 532: 137–155.

    Article  CAS  PubMed  Google Scholar 

  • Barber LJ, Youds JL, Ward JD, McIlwraith MJ, O'Neil NJ, Petalcorin MI et al. (2008). RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135: 261–271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK . (2000). The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275: 23899–23903.

    Article  CAS  PubMed  Google Scholar 

  • Bridge WL, Vandenberg CJ, Franklin RJ, Hiom K . (2005). The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nat Genet 37: 953–957.

    Article  CAS  PubMed  Google Scholar 

  • Bugreev DV, Yu X, Egelman EH, Mazin AV . (2007). Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes Dev 21: 3085–3094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S et al. (2004). The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci USA 101: 2357–2362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cantor SB, Andreassen PR . (2006). Assessing the link between BACH1 and BRCA1 in the FA pathway. Cell Cycle 5: 164–167.

    Article  CAS  PubMed  Google Scholar 

  • Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S et al. (2001). BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105: 149–160.

    Article  CAS  PubMed  Google Scholar 

  • Delacote F, Deriano L, Lambert S, Bertrand P, Saintigny Y, Lopez BS . (2007). Chronic exposure to sublethal doses of radiation mimetic Zeocin selects for clones deficient in homologous recombination. Mutat Res 615: 125–133.

    Article  CAS  PubMed  Google Scholar 

  • Dronkert ML, Kanaar R . (2001). Repair of DNA interstrand cross-links. Mutat Res 486: 217–247.

    Article  CAS  PubMed  Google Scholar 

  • Dupaigne P, Le Breton C, Fabre F, Gangloff S, Le Cam E, Veaute X . (2008). The Srs2 helicase activity is stimulated by Rad51 filaments on dsDNA: implications for crossover incidence during mitotic recombination. Mol Cell 29: 243–254.

    Article  CAS  PubMed  Google Scholar 

  • Eelen G, Vanden Bempt I, Verlinden L, Drijkoningen M, Smeets A, Neven P et al. (2008). Expression of the BRCA1-interacting protein Brip1/BACH1/FANCJ is driven by E2F and correlates with human breast cancer malignancy. Oncogene 27: 4233–4241.

    Article  CAS  PubMed  Google Scholar 

  • Gupta R, Sharma S, Sommers JA, Jin Z, Cantor SB, Brosh Jr RM . (2005). Analysis of the DNA substrate specificity of the human BACH1 helicase associated with breast cancer. J Biol Chem 280: 25450–25460.

    Article  CAS  PubMed  Google Scholar 

  • Hinz JM, Nham PB, Salazar EP, Thompson LH . (2006). The Fanconi anemia pathway limits the severity of mutagenesis. DNA Repair (Amst) 5: 875–884.

    Article  CAS  Google Scholar 

  • Kannouche P, Broughton BC, Volker M, Hanaoka F, Mullenders LH, Lehmann AR . (2001). Domain structure, localization, and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells. Genes Dev 15: 158–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannouche PL, Lehmann AR . (2004). Ubiquitination of PCNA and the polymerase switch in human cells. Cell Cycle 3: 1011–1013.

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto T, Araki K, Sonoda E, Yamashita YM, Harada K, Kikuchi K et al. (2005). Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell 20: 793–799.

    Article  CAS  PubMed  Google Scholar 

  • Kim H, Chen J . (2008). New players in the BRCA1-mediated DNA damage responsive pathway. Mol Cells 25: 457–461.

    CAS  PubMed  Google Scholar 

  • Levitus M, Waisfisz Q, Godthelp BC, Vries YD, Hussain S, Wiegant WW et al. (2005). The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 37: 934–935.

    Article  CAS  PubMed  Google Scholar 

  • Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P et al. (2005). The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37: 931–933.

    Article  CAS  PubMed  Google Scholar 

  • Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S et al. (2005). BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8: 255–265.

    Article  CAS  PubMed  Google Scholar 

  • McIlwraith MJ, Vaisman A, Liu Y, Fanning E, Woodgate R, West SC . (2005). Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination. Mol Cell 20: 783–792.

    Article  CAS  PubMed  Google Scholar 

  • Mechanic LE, Frankel BA, Matson SW . (2000). Escherichia coli MutL loads DNA helicase II onto DNA. J Biol Chem 275: 38337–38346.

    Article  CAS  PubMed  Google Scholar 

  • Moynahan ME, Chiu JW, Koller BH, Jasin M . (1999). Brca1 controls homology-directed DNA repair. Mol Cell 4: 511–518.

    Article  CAS  PubMed  Google Scholar 

  • Moynahan ME, Pierce AJ, Jasin M . (2001). BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7: 263–272.

    Article  CAS  PubMed  Google Scholar 

  • Niedernhofer LJ, Lalai AS, Hoeijmakers JH . (2005). Fanconi anemia (cross)linked to DNA repair. Cell 123: 1191–1198.

    Article  CAS  PubMed  Google Scholar 

  • Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ . (2004). The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell 15: 607–620.

    Article  CAS  PubMed  Google Scholar 

  • Nojima K, Hochegger H, Saberi A, Fukushima T, Kikuchi K, Yoshimura M et al. (2005). Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65: 11704–11711.

    Article  CAS  PubMed  Google Scholar 

  • Papouli E, Chen S, Davies AA, Huttner D, Krejci L, Sung P et al. (2005). Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol Cell 19: 123–133.

    Article  CAS  PubMed  Google Scholar 

  • Patel KJ, Joenje H . (2007). Fanconi anemia and DNA replication repair. DNA Repair (Amst) 6: 885–890.

    Article  CAS  Google Scholar 

  • Peng M, Litman R, Xie J, Sharma S, Brosh Jr RM, Cantor SB . (2007). The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J 26: 3238–3249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierce AJ, Johnson RD, Thompson LH, Jasin M . (1999). XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev 13: 2633–2638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prakash S, Johnson RE, Prakash L . (2005). Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem 74: 317–353.

    Article  CAS  PubMed  Google Scholar 

  • Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R 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 

  • Shen X, Do H, Li Y, Chung WH, Tomasz M, de Winter JP et al. (2009). Recruitment of fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication. Mol Cell 35: 716–723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinclair CS, Rowley M, Naderi A, Couch FJ . (2003). The 17q23 amplicon and breast cancer. Breast Cancer Res Treat 78: 313–322.

    Article  CAS  PubMed  Google Scholar 

  • Sommers JA, Rawtani N, Gupta R, Bugreev DV, Mazin AV, Cantor SB et al. (2009). FANCJ uses its motor ATPase to disrupt protein-DNA complexes, unwind triplexes, and inhibit rad51 strand exchange. J Biol Chem 284: 7505–7517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W . (2007). Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8: 735–748.

    Article  CAS  PubMed  Google Scholar 

  • Watanabe K, Tateishi S, Kawasuji M, Tsurimoto T, Inoue H, Yamaizumi M . (2004). Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J 23: 3886–3896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu X, Chini CC, He M, Mer G, Chen J . (2003). The BRCT domain is a phospho-protein binding domain. Science 302: 639–642.

    Article  CAS  PubMed  Google Scholar 

  • Zheng H, Wang X, Warren AJ, Legerski RJ, Nairn RS, Hamilton JW et al. (2003). Nucleotide excision repair- and polymerase eta-mediated error-prone removal of mitomycin C interstrand cross-links. Mol Cell Biol 23: 754–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Larry Thompson, Alan Lehmann, and Roger Greenberg for critical comments. We also thank Maria Jasin for the DR-U2OS cells and Alan Lehmann for the XPV-vector and polη-complemented lines as well as polη-GFP construct, Hans Joenje for FA-J cells, and Claire Baldwin for readership comments. This study was supported by NIH R01 CA129514-01A1 and from charitable contributions from Mr and Mrs Edward T Vitone Jr.

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  1. J Xie, R Litman and S Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA

    J Xie, R Litman, S Wang, M Peng, S Guillemette, T Rooney & S B Cantor

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  1. J Xie
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Correspondence to S B Cantor.

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Xie, J., Litman, R., Wang, S. et al. Targeting the FANCJ–BRCA1 interaction promotes a switch from recombination to polη-dependent bypass. Oncogene 29, 2499–2508 (2010). https://doi.org/10.1038/onc.2010.18

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