BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution.

Cohen, S.; Guenole, A.; Marnef, A.; Clouaire, T.; Puget, N.; Rocher, V.; Arnould, C.; Aguirrebengoa, M.; Genais, M.; Verneka, D.; Mourad, R.; Borde, V.; Legube, G.

doi:10.1101/2020.05.13.093112

bioRxiv · 10.1101/2020.05.13.093112

BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution.

Cohen, S.·Guenole, A.·Marnef, A.·Clouaire, T.·Puget, N.·Rocher, V.·Arnould, C.·Aguirrebengoa, M.·Genais, M.·Verneka, D.·Mourad, R.·Borde, V.·Legube, G.

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Abstract

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggest that DNA Double-Strand Breaks arising in genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loops accumulation and dissolution. Here, we uncovered a critical function of 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 a R-loop dissolution-deficient background BLM switches from promoting Homologous Recombination to promoting Break-Induced Replication (BIR), which strongly impairs cell viability. Altogether our work unveils a role for BLM in BIR at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at these transcription-associated DSBs.

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Cohen, S., Guenole, A., Marnef, A., Clouaire, T., Puget, N., Rocher, V., Arnould, C., Aguirrebengoa, M., Genais, M., Verneka, D., Mourad, R., Borde, V., Legube, G.. 2020-05-15. BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution.. https://doi.org/10.1101/2020.05.13.093112

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