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A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation

Author

Listed:
  • S. Cohen

    (Université de Toulouse, UT3)

  • A. Guenolé

    (Université de Toulouse, UT3)

  • I. Lazar

    (Université de Toulouse, UT3)

  • A. Marnef

    (Université de Toulouse, UT3)

  • T. Clouaire

    (Université de Toulouse, UT3)

  • D. V. Vernekar

    (Dynamics of Genetic Information)

  • N. Puget

    (Université de Toulouse, UT3)

  • V. Rocher

    (Université de Toulouse, UT3)

  • C. Arnould

    (Université de Toulouse, UT3)

  • M. Aguirrebengoa

    (Université de Toulouse, UT3)

  • M. Genais

    (Université de Toulouse, UT3)

  • N. Firmin

    (Université de Toulouse, UT3)

  • R. A. Shamanna

    (National Institutes of Health)

  • R. Mourad

    (Université de Toulouse, UT3)

  • V. A. Bohr

    (National Institutes of Health)

  • V. Borde

    (Dynamics of Genetic Information)

  • G. Legube

    (Université de Toulouse, UT3)

Abstract

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.

Suggested Citation

  • S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29629-2
    DOI: 10.1038/s41467-022-29629-2
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