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BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance

Author

Listed:
  • Yifan Wang

    (Fox Chase Cancer Center)

  • Andrea J. Bernhardy

    (Fox Chase Cancer Center)

  • Joseph Nacson

    (Fox Chase Cancer Center
    Temple University)

  • John J. Krais

    (Fox Chase Cancer Center)

  • Yin-Fei Tan

    (Fox Chase Cancer Center)

  • Emmanuelle Nicolas

    (Fox Chase Cancer Center
    Fox Chase Cancer Center)

  • Marc R. Radke

    (University of Washington)

  • Elizabeth Handorf

    (Fox Chase Cancer Center)

  • Alba Llop-Guevara

    (Vall d’Hebron Institute of Oncology)

  • Judith Balmaña

    (Vall d’Hebron Institute of Oncology)

  • Elizabeth M. Swisher

    (University of Washington)

  • Violeta Serra

    (Vall d’Hebron Institute of Oncology)

  • Suraj Peri

    (Fox Chase Cancer Center)

  • Neil Johnson

    (Fox Chase Cancer Center)

Abstract

BRCA1 mutant carcinomas are sensitive to PARP inhibitor (PARPi) therapy; however, resistance arises. BRCA1 BRCT domain mutant proteins do not fold correctly and are subject to proteasomal degradation, resulting in PARPi sensitivity. In this study, we show that cell lines and patient-derived tumors, with highly disruptive BRCT domain mutations, have readily detectable BRCA1 protein expression, and are able to proliferate in the presence of PARPi. Peptide analyses reveal that chemo-resistant cancers contain residues encoded by BRCA1 intron 15. Mechanistically, cancers with BRCT domain mutations harbor BRCA1 gene breakpoints within or adjacent to Alu elements in intron 15; producing partial gene duplications, inversions and translocations, and terminating transcription prior to the mutation-containing BRCT domain. BRCA1 BRCT domain-deficient protein isoforms avoid mutation-induced proteasomal degradation, support homology-dependent DNA repair, and promote PARPi resistance. Taken together, Alu-mediated BRCA1 gene rearrangements are responsible for generating hypomorphic proteins, and may represent a biomarker of PARPi resistance.

Suggested Citation

  • Yifan Wang & Andrea J. Bernhardy & Joseph Nacson & John J. Krais & Yin-Fei Tan & Emmanuelle Nicolas & Marc R. Radke & Elizabeth Handorf & Alba Llop-Guevara & Judith Balmaña & Elizabeth M. Swisher & Vi, 2019. "BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13530-6
    DOI: 10.1038/s41467-019-13530-6
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    Cited by:

    1. John J. Krais & David J. Glass & Ilse Chudoba & Yifan Wang & Wanjuan Feng & Dennis Simpson & Pooja Patel & Zemin Liu & Ryan Neumann-Domer & Robert G. Betsch & Andrea J. Bernhardy & Alice M. Bradbury &, 2023. "Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Takuya Tsujino & Tomoaki Takai & Kunihiko Hinohara & Fu Gui & Takeshi Tsutsumi & Xiao Bai & Chenkui Miao & Chao Feng & Bin Gui & Zsofia Sztupinszki & Antoine Simoneau & Ning Xie & Ladan Fazli & Xuesen, 2023. "CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Richard Taylor & Fursham Hamid & Triona Fielding & Patricia M. Gordon & Megan Maloney & Eugene V. Makeyev & Corinne Houart, 2022. "Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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