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

Abstract : 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.
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https://hal-cnrs.archives-ouvertes.fr/hal-03842463
Contributor : Aline Marnef Connect in order to contact the contributor
Submitted on : Monday, November 7, 2022 - 3:40:43 PM
Last modification on : Wednesday, November 23, 2022 - 11:58:31 AM

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S. Cohen, A. Guenolé, I. Lazar, A. Marnef, T. Clouaire, et al.. A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation. Nature Communications, 2022, 13 (1), pp.2012. ⟨10.1038/s41467-022-29629-2⟩. ⟨hal-03842463⟩

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