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

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. Borde and G. Legube ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-15

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.

Date: 2022
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DOI: 10.1038/s41467-022-29629-2

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