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DNA nicks induce mutational signatures associated with BRCA1 deficiency

Author

Listed:
  • Yi-Li Feng

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Qian Liu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Ruo-Dan Chen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Si-Cheng Liu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Zhi-Cheng Huang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Kun-Ming Liu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • Xiao-Ying Yang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

  • An-Yong Xie

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine and Zhejiang University Cancer Center)

Abstract

Analysis of human cancer genome sequences has revealed specific mutational signatures associated with BRCA1-deficient tumors, but the underlying mechanisms remain poorly understood. Here, we show that one-ended DNA double strand breaks (DSBs) converted from CRISPR/Cas9-induced nicks by DNA replication, not two-ended DSBs, cause more characteristic chromosomal aberrations and micronuclei in Brca1-deficient cells than in wild-type cells. BRCA1 is required for efficient homologous recombination of these nick-converted DSBs and suppresses bias towards long tract gene conversion and tandem duplication (TD) mediated by two-round strand invasion in a replication strand asymmetry. However, aberrant repair of these nick-converted one-ended DSBs, not that of two-ended DSBs in Brca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those in BRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated with BRCA1 deficiency in cancer and the underlying mechanisms.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32011-x
    DOI: 10.1038/s41467-022-32011-x
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