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ZFP281-BRCA2 prevents R-loop accumulation during DNA replication

Author

Listed:
  • Yan Wang

    (Southeast University)

  • Binbin Ma

    (Tongji University)

  • Xiaoxu Liu

    (Southeast University)

  • Ge Gao

    (The University of Hong Kong)

  • Zhuanzhuan Che

    (Southeast University)

  • Menghan Fan

    (Southeast University)

  • Siyan Meng

    (Southeast University)

  • Xiru Zhao

    (Southeast University)

  • Rio Sugimura

    (The University of Hong Kong)

  • Hua Cao

    (Affiliated Hospital of Fujian Medical University)

  • Zhongjun Zhou

    (The University of Hong Kong)

  • Jing Xie

    (Tongji University)

  • Chengqi Lin

    (Affiliated Hospital of Fujian Medical University
    Southeast University
    Southeast University)

  • Zhuojuan Luo

    (Southeast University
    Southeast University)

Abstract

R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Depletion of BRCA2 leads to aberrant R-loop accumulation, contributing to genome instability. Here, we show that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells. ZFP281 depletion reduces PCNA levels on chromatin and impairs DNA replication. Mechanistically, we demonstrate that ZFP281 can interact with BRCA2, and that BRCA2 is enriched at G/C-rich promoters and requires both ZFP281 and PRC2 for its proper recruitment to the bivalent chromatin at the genome-wide scale. Furthermore, depletion of ZFP281 or BRCA2 leads to accumulation of R-loops over the bivalent regions, and compromises activation of the developmental genes by retinoic acid during stem cell differentiation. In summary, our results reveal that ZFP281 recruits BRCA2 to the bivalent chromatin regions to ensure proper progression of DNA replication through preventing persistent R-loops.

Suggested Citation

  • Yan Wang & Binbin Ma & Xiaoxu Liu & Ge Gao & Zhuanzhuan Che & Menghan Fan & Siyan Meng & Xiru Zhao & Rio Sugimura & Hua Cao & Zhongjun Zhou & Jing Xie & Chengqi Lin & Zhuojuan Luo, 2022. "ZFP281-BRCA2 prevents R-loop accumulation during DNA replication," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31211-9
    DOI: 10.1038/s41467-022-31211-9
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    References listed on IDEAS

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    1. Qi-Long Ying & Jason Wray & Jennifer Nichols & Laura Batlle-Morera & Bradley Doble & James Woodgett & Philip Cohen & Austin Smith, 2008. "The ground state of embryonic stem cell self-renewal," Nature, Nature, vol. 453(7194), pages 519-523, May.
    2. Prasun Chakraborty & Jeffrey T. J. Huang & Kevin Hiom, 2018. "DHX9 helicase promotes R-loop formation in cells with impaired RNA splicing," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Vaibhav Bhatia & Sonia I. Barroso & María L. García-Rubio & Emanuela Tumini & Emilia Herrera-Moyano & Andrés Aguilera, 2014. "BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2," Nature, Nature, vol. 511(7509), pages 362-365, July.
    4. Luca Pellegrini & David S. Yu & Thomas Lo & Shubha Anand & MiYoung Lee & Tom L. Blundell & Ashok R. Venkitaraman, 2002. "Insights into DNA recombination from the structure of a RAD51–BRCA2 complex," Nature, Nature, vol. 420(6913), pages 287-293, November.
    5. Konstantina Skourti-Stathaki & Kinga Kamieniarz-Gdula & Nicholas J. Proudfoot, 2014. "R-loops induce repressive chromatin marks over mammalian gene terminators," Nature, Nature, vol. 516(7531), pages 436-439, December.
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    1. 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.

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