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DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination

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  • Prasun Chakraborty

    (Division of Cellular Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee)

  • Kevin Hiom

    (Division of Cellular Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee)

Abstract

Double stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.

Suggested Citation

  • Prasun Chakraborty & Kevin Hiom, 2021. "DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24341-z
    DOI: 10.1038/s41467-021-24341-z
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    Cited by:

    1. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Elias Einig & Chao Jin & Valentina Andrioletti & Boris Macek & Nikita Popov, 2023. "RNAPII-dependent ATM signaling at collisions with replication forks," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Bing-Ze Yang & Mei-Yin Liu & Kuan-Lin Chiu & Yuh-Ling Chien & Ching-An Cheng & Yu-Lin Chen & Li-Yu Tsui & Keng-Ru Lin & Hsueh-Ping Catherine Chu & Ching-Shyi Peter Wu, 2024. "DHX9 SUMOylation is required for the suppression of R-loop-associated genome instability," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Victoria O. Shender & Ksenia S. Anufrieva & Polina V. Shnaider & Georgij P. Arapidi & Marat S. Pavlyukov & Olga M. Ivanova & Irina K. Malyants & Grigory A. Stepanov & Evgenii Zhuravlev & Rustam H. Zig, 2024. "Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-26, December.

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