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ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB

Author

Listed:
  • Yaqun Teng

    (Tsinghua University
    University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Tribhuwan Yadav

    (Harvard Medical School)

  • Meihan Duan

    (Tsinghua University
    University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Jun Tan

    (UPMC Hillman Cancer Center)

  • Yufei Xiang

    (University of Pittsburgh School of Medicine)

  • Boya Gao

    (UPMC Hillman Cancer Center)

  • Jianquan Xu

    (University of Pittsburgh)

  • Zhuobin Liang

    (Yale Medical School)

  • Yang Liu

    (University of Pittsburgh)

  • Satoshi Nakajima

    (University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Yi Shi

    (University of Pittsburgh School of Medicine)

  • Arthur S. Levine

    (University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Lee Zou

    (Harvard Medical School
    Harvard Medical School)

  • Li Lan

    (University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center
    Harvard Medical School
    Harvard Medical School)

Abstract

Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB in turn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSB displays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced R loops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51 axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.

Suggested Citation

  • Yaqun Teng & Tribhuwan Yadav & Meihan Duan & Jun Tan & Yufei Xiang & Boya Gao & Jianquan Xu & Zhuobin Liang & Yang Liu & Satoshi Nakajima & Yi Shi & Arthur S. Levine & Lee Zou & Li Lan, 2018. "ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06586-3
    DOI: 10.1038/s41467-018-06586-3
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    Cited by:

    1. 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.
    2. Martin Andrs & Henriette Stoy & Barbora Boleslavska & Nagaraja Chappidi & Radhakrishnan Kanagaraj & Zuzana Nascakova & Shruti Menon & Satyajeet Rao & Anna Oravetzova & Jana Dobrovolna & Kalpana Surend, 2023. "Excessive reactive oxygen species induce transcription-dependent replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Manisha Jalan & Aman Sharma & Xin Pei & Nils Weinhold & Erika S. Buechelmaier & Yingjie Zhu & Sana Ahmed-Seghir & Abhirami Ratnakumar & Melody Bona & Niamh McDermott & Joan Gomez-Aguilar & Kyrie S. An, 2024. "RAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. 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.
    5. 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.
    6. Yuxin Huang & Wenjing Li & Tzeh Foo & Jae-Hoon Ji & Bo Wu & Nozomi Tomimatsu & Qingming Fang & Boya Gao & Melissa Long & Jingfei Xu & Rouf Maqbool & Bipasha Mukherjee & Tengyang Ni & Salvador Alejo & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Xuan Zhang & Jun Xu & Jing Hu & Sitao Zhang & Yajing Hao & Dongyang Zhang & Hao Qian & Dong Wang & Xiang-Dong Fu, 2024. "Cockayne Syndrome Linked to Elevated R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Shinta Saito & Noritaka Adachi, 2024. "Characterization and regulation of cell cycle-independent noncanonical gene targeting," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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