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RNA transcripts stimulate homologous recombination by forming DR-loops

Author

Listed:
  • Jian Ouyang

    (Harvard Medical School)

  • Tribhuwan Yadav

    (Harvard Medical School)

  • Jia-Min Zhang

    (Harvard Medical School)

  • Haibo Yang

    (Harvard Medical School
    Harvard Medical School)

  • Esther Rheinbay

    (Harvard Medical School)

  • Hongshan Guo

    (Harvard Medical School
    Massachusetts General Hospital)

  • Daniel A. Haber

    (Harvard Medical School
    Massachusetts General Hospital)

  • Li Lan

    (Harvard Medical School
    Harvard Medical School)

  • Lee Zou

    (Harvard Medical School
    Harvard Medical School)

Abstract

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1–3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4–10, but how transcription promotes HR is poorly understood. Here we develop an assay to assess the effect of local transcription on HR. Using this assay, we find that transcription stimulates HR to a substantial extent. Tethering RNA transcripts to the vicinity of DSBs recapitulates the effects of local transcription, which suggests that transcription enhances HR through RNA transcripts. Tethered RNA transcripts stimulate HR in a sequence- and orientation-dependent manner, indicating that they function by forming DNA–RNA hybrids. In contrast to most HR proteins, RAD51-associated protein 1 (RAD51AP1) only promotes HR when local transcription is active. RAD51AP1 drives the formation of R-loops in vitro and is required for tethered RNAs to stimulate HR in cells. Notably, RAD51AP1 is necessary for the DSB-induced formation of DNA–RNA hybrids in donor DNA, linking R-loops to D-loops. In vitro, RAD51AP1-generated R-loops enhance the RAD51-mediated formation of D-loops locally and give rise to intermediates that we term ‘DR-loops’, which contain both DNA–DNA and DNA–RNA hybrids and favour RAD51 function. Thus, at DSBs in transcribed regions, RAD51AP1 promotes the invasion of RNA transcripts into donor DNA, and stimulates HR through the formation of DR-loops.

Suggested Citation

  • Jian Ouyang & Tribhuwan Yadav & Jia-Min Zhang & Haibo Yang & Esther Rheinbay & Hongshan Guo & Daniel A. Haber & Li Lan & Lee Zou, 2021. "RNA transcripts stimulate homologous recombination by forming DR-loops," Nature, Nature, vol. 594(7862), pages 283-288, June.
  • Handle: RePEc:nat:nature:v:594:y:2021:i:7862:d:10.1038_s41586-021-03538-8
    DOI: 10.1038/s41586-021-03538-8
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    Citations

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    Cited by:

    1. John K. Barrows & Baicheng Lin & Colleen E. Quaas & George Fullbright & Elizabeth N. Wallace & David T. Long, 2022. "BRD4 promotes resection and homology-directed repair of DNA double-strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Chia-Yu Guh & Hong-Jhih Shen & Liv WeiChien Chen & Pei-Chen Chiu & I-Hsin Liao & Chen-Chia Lo & Yunfei Chen & Yu-Hung Hsieh & Ting-Chia Chang & Chien-Ping Yen & Yi-Yun Chen & Tom Wei-Wu Chen & Liuh-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Dayana E. Salas-Leiva & Eelco C. Tromer & Bruce A. Curtis & Jon Jerlström-Hultqvist & Martin Kolisko & Zhenzhen Yi & Joan S. Salas-Leiva & Lucie Gallot-Lavallée & Shelby K. Williams & Geert J. P. L. K, 2021. "Genomic analysis finds no evidence of canonical eukaryotic DNA processing complexes in a free-living protist," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Yumin Wang & Boya Gao & Luyuan Zhang & Xudong Wang & Xiaolan Zhu & Haibo Yang & Fengqi Zhang & Xueping Zhu & Badi Zhou & Sean Yao & Aiko Nagayama & Sanghoon Lee & Jian Ouyang & Siang-Boon Koh & Eric L, 2024. "Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Guangxue Liu & Jimin Li & Boxue He & Jiaqi Yan & Jingyu Zhao & Xuejie Wang & Xiaocong Zhao & Jingyan Xu & Yeyao Wu & Simin Zhang & Xiaoli Gan & Chun Zhou & Xiangpan Li & Xinghua Zhang & Xuefeng Chen, 2023. "Bre1/RNF20 promotes Rad51-mediated strand exchange and antagonizes the Srs2/FBH1 helicases," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Haibo Yang & Emily M. Lachtara & Xiaojuan Ran & Jessica Hopkins & Parasvi S. Patel & Xueping Zhu & Yao Xiao & Laiyee Phoon & Boya Gao & Lee Zou & Michael S. Lawrence & Li Lan, 2023. "The RNA m5C modification in R-loops as an off switch of Alt-NHEJ," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. 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, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Joseph Walton & Angel S. N. Ng & Karen Arevalo & Anthony Apostoli & Jalna Meens & Christina Karamboulas & Jonathan St-Germain & Panagiotis Prinos & Julia Dmytryshyn & Eric Chen & Cheryl H. Arrowsmith , 2024. "PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    9. Meng Xu & Dulmi Senanayaka & Rongwei Zhao & Tafadzwa Chigumira & Astha Tripathi & Jason Tones & Rachel M. Lackner & Anne R. Wondisford & Laurel N. Moneysmith & Alexander Hirschi & Sara Craig & Sahar A, 2024. "TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    10. Zhen Wang & Claudia M. Castillo-González & Changjiang Zhao & Chun-Yip Tong & Changhao Li & Songxiao Zhong & Zhiyang Liu & Kaili Xie & Jiaying Zhu & Zhongshou Wu & Xu Peng & Yannick Jacob & Scott D. Mi, 2023. "H3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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