1. A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation.
- Author
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Cohen, S, Guenolé, A, Lazar, I, Marnef, A, Clouaire, T, Vernekar, DV, Puget, N, Rocher, V, Arnould, C, Aguirrebengoa, M, Genais, M, Firmin, N, Shamanna, RA, Mourad, R, Bohr, VA, Borde, V, and Legube, G
- Subjects
Chromatin ,Humans ,DNA ,RNA ,DNA Repair ,RecQ Helicases ,DNA Breaks ,Double-Stranded ,Recombinational DNA Repair ,Genetics ,Rare Diseases ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Cancer - 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.
- Published
- 2022