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BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining

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  • J. A. Kamp

    (Leiden University Medical Center)

  • R. Schendel

    (Leiden University Medical Center)

  • I. W. Dilweg

    (Leiden University Medical Center)

  • M. Tijsterman

    (Leiden University Medical Center
    Leiden University)

Abstract

Failure to preserve the integrity of the genome is a hallmark of cancer. Recent studies have revealed that loss of the capacity to repair DNA breaks via homologous recombination (HR) results in a mutational profile termed BRCAness. The enzymatic activity that repairs HR substrates in BRCA-deficient conditions to produce this profile is currently unknown. We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We identify polymerase theta-mediated end-joining (TMEJ) to be responsible: knocking out polq-1 suppresses the accumulation of deletions and tandem duplications in brc-1 and brd-1 animals. We find no additional back-up repair in HR and TMEJ compromised animals; non-homologous end-joining does not affect BRCAness. The notion that TMEJ acts as an alternative to HR, promoting the genome alteration of HR-deficient cells, supports the idea that polymerase theta is a promising therapeutic target for HR-deficient tumours.

Suggested Citation

  • J. A. Kamp & R. Schendel & I. W. Dilweg & M. Tijsterman, 2020. "BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17455-3
    DOI: 10.1038/s41467-020-17455-3
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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. Yi-Li Feng & Qian Liu & Ruo-Dan Chen & Si-Cheng Liu & Zhi-Cheng Huang & Kun-Ming Liu & Xiao-Ying Yang & An-Yong Xie, 2022. "DNA nicks induce mutational signatures associated with BRCA1 deficiency," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Panpan Zhang & Assane Mbodj & Abirami Soundiramourtty & Christel Llauro & Alain Ghesquière & Mathieu Ingouff & R. Keith Slotkin & Frédéric Pontvianne & Marco Catoni & Marie Mirouze, 2023. "Extrachromosomal circular DNA and structural variants highlight genome instability in Arabidopsis epigenetic mutants," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. J. A. Kamp & B. B. L. G. Lemmens & R. J. Romeijn & S. C. Changoer & R. Schendel & M. Tijsterman, 2021. "Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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