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

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Cohen, S. | Guénolé, Aude | Lazar, I. | Marnef, A. | Clouaire, T. | Vernekar, D. | Puget, Nadine | Rocher, V. | Arnould, Coline | Aguirrebengoa, Marion | Genais, M. | Firmin, N. | Shamanna, R. | Mourad, Raphaël | Bohr, V. | Borde, V. | Legube, G. | Rocher, Vincent

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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