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Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ

Author

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  • Wei Yu

    (Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur)

  • Chloé Lescale

    (Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur)

  • Loelia Babin

    (Genome Dynamics in the Immune System Laboratory, Equipe Labellisée Ligue Contre Le Cancer, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • Marie Bedora-Faure

    (Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur)

  • Hélène Lenden-Hasse

    (Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur)

  • Ludivine Baron

    (Immunobiology of Infection Unit, INSERM U1221, Institut Pasteur)

  • Caroline Demangel

    (Immunobiology of Infection Unit, INSERM U1221, Institut Pasteur)

  • José Yelamos

    (Cancer Research Program, Hospital del Mar Medical Research Institute)

  • Erika Brunet

    (Genome Dynamics in the Immune System Laboratory, Equipe Labellisée Ligue Contre Le Cancer, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • Ludovic Deriano

    (Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur)

Abstract

The alternative non-homologous end-joining (NHEJ) pathway promotes DNA double-strand break (DSB) repair in cells deficient for NHEJ or homologous recombination, suggesting that it operates at all stages of the cell cycle. Here, we use an approach in which DNA breaks can be induced in G1 cells and their repair tracked, enabling us to show that joining of DSBs is not functional in G1-arrested XRCC4-deficient cells. Cell cycle entry into S-G2/M restores DSB repair by Pol θ-dependent and PARP1-independent alternative NHEJ with repair products bearing kilo-base long DNA end resection, micro-homologies and chromosome translocations. We identify a synthetic lethal interaction between XRCC4 and Pol θ under conditions of G1 DSBs, associated with accumulation of unresolved DNA ends in S-G2/M. Collectively, our results support the conclusion that the repair of G1 DSBs progressing to S-G2/M by alternative NHEJ drives genomic instability and represent an attractive target for future DNA repair-based cancer therapies.

Suggested Citation

  • Wei Yu & Chloé Lescale & Loelia Babin & Marie Bedora-Faure & Hélène Lenden-Hasse & Ludivine Baron & Caroline Demangel & José Yelamos & Erika Brunet & Ludovic Deriano, 2020. "Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19060-w
    DOI: 10.1038/s41467-020-19060-w
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    Cited by:

    1. Estelle Vincendeau & Wenming Wei & Xuefei Zhang & Cyril Planchais & Wei Yu & Hélène Lenden-Hasse & Thomas Cokelaer & Juliana Pipoli da Fonseca & Hugo Mouquet & David J. Adams & Frederick W. Alt & Step, 2022. "SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Diana Rubio-Contreras & Fernando Gómez-Herreros, 2023. "TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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