IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33356-z.html
   My bibliography  Save this article

Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs

Author

Listed:
  • Liang Chen

    (University of Science and Technology of China)

  • Yucong Wang

    (University of Science and Technology of China)

  • Jiamei Lin

    (Chongqing University
    Chongqing University)

  • Zhenxing Song

    (Chongqing University
    Chongqing University)

  • Qinwei Wang

    (University of Science and Technology of China)

  • Wenfang Zhao

    (University of Science and Technology of China)

  • Yan Wang

    (Wenzhou Medical University
    State Key Laboratory of Optometry, Ophthalmology, and Visual Science)

  • Xiaoyu Xiu

    (Wenzhou Medical University
    State Key Laboratory of Optometry, Ophthalmology, and Visual Science)

  • Yuqi Deng

    (University of Science and Technology of China)

  • Xiuzhi Li

    (University of Science and Technology of China)

  • Qiqi Li

    (University of Science and Technology of China)

  • Xiaolin Wang

    (University of Science and Technology of China)

  • Jingxin Li

    (University of Science and Technology of China)

  • Xu Liu

    (University of Science and Technology of China)

  • Kunpeng Liu

    (Tsinghua University)

  • Jincong Zhou

    (Tsinghua University)

  • Kuan Li

    (Tsinghua University)

  • Yuchan Liu

    (University of Science and Technology of China)

  • Shanhui Liao

    (University of Science and Technology of China)

  • Qin Deng

    (Chongqing University)

  • Chao Xu

    (University of Science and Technology of China)

  • Qianwen Sun

    (Tsinghua University)

  • Shengzhou Wu

    (Wenzhou Medical University
    State Key Laboratory of Optometry, Ophthalmology, and Visual Science)

  • Kaiming Zhang

    (University of Science and Technology of China)

  • Min-Xin Guan

    (Zhejiang University School of Medicine)

  • Tianhua Zhou

    (Zhejiang University)

  • Fei Sun

    (Zhejiang University School of Medicine)

  • Xiujun Cai

    (Zhejiang University School of Medicine)

  • Chuan Huang

    (Chongqing University
    Chongqing University)

  • Ge Shan

    (University of Science and Technology of China
    Zhejiang University)

Abstract

Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans. Exonic circRNAs (ecircRNAs) with higher expression levels, larger length, and lower GC content are more sensitive to XPO4 deficiency. Cellular insufficiency of XPO4 leads to nuclear circRNA accumulation, circRNA:DNA (ciR-loop) formation, linear RNA:DNA (liR-loop) buildup, and DNA damage. DDX39 known to modulate circRNA export can resolve ciR-loop, and splicing factors involved in the biogenesis of circRNAs can also affect the levels of ciR-loop. Testis and brain are two organs with high abundance of circRNAs, and insufficient XPO4 levels are detrimental, as Xpo4 heterozygous mice display male infertility and neural phenotypes. Increased levels of ciR-loop, R-loop, and DNA damage along with decreased cell numbers are observed in testis and hippocampus of Xpo4 heterozygotes. This study sheds light on the understandings of mechanism of circRNA export and reveals the significance of efficient nuclear export of circRNAs in cellular physiology.

Suggested Citation

  • Liang Chen & Yucong Wang & Jiamei Lin & Zhenxing Song & Qinwei Wang & Wenfang Zhao & Yan Wang & Xiaoyu Xiu & Yuqi Deng & Xiuzhi Li & Qiqi Li & Xiaolin Wang & Jingxin Li & Xu Liu & Kunpeng Liu & Jincon, 2022. "Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33356-z
    DOI: 10.1038/s41467-022-33356-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33356-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33356-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. David Grünwald & Robert H. Singer & Michael Rout, 2011. "Nuclear export dynamics of RNA–protein complexes," Nature, Nature, vol. 475(7356), pages 333-341, July.
    3. Nicolas Viphakone & Guillaume M. Hautbergue & Matthew Walsh & Chung-Te Chang & Arthur Holland & Eric G. Folco & Robin Reed & Stuart A. Wilson, 2012. "TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export," Nature Communications, Nature, vol. 3(1), pages 1-14, January.
    4. Yoav Lubelsky & Igor Ulitsky, 2018. "Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells," Nature, Nature, vol. 555(7694), pages 107-111, March.
    5. Yafei Yin & J. Yuyang Lu & Xuechun Zhang & Wen Shao & Yanhui Xu & Pan Li & Yantao Hong & Li Cui & Ge Shan & Bin Tian & Qiangfeng Cliff Zhang & Xiaohua Shen, 2020. "U1 snRNP regulates chromatin retention of noncoding RNAs," Nature, Nature, vol. 580(7801), pages 147-150, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Aleix Bayona-Feliu & Emilia Herrera-Moyano & Nibal Badra-Fajardo & Iván Galván-Femenía & María Eugenia Soler-Oliva & Andrés Aguilera, 2023. "The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. 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.
    3. Ken-ichi Fujita & Misa Ito & Midori Irie & Kotaro Harada & Naoko Fujiwara & Yuya Ikeda & Hanae Yoshioka & Tomohiro Yamazaki & Masaki Kojima & Bunzo Mikami & Akila Mayeda & Seiji Masuda, 2024. "Structural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Arun Prakash Mishra & Suzanne A. Hartford & Sounak Sahu & Kimberly Klarmann & Rajani Kant Chittela & Kajal Biswas & Albert B. Jeon & Betty K. Martin & Sandra Burkett & Eileen Southon & Susan Reid & Ma, 2022. "BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Charles Limouse & Owen K. Smith & David Jukam & Kelsey A. Fryer & William J. Greenleaf & Aaron F. Straight, 2023. "Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Maya Ron & Igor Ulitsky, 2022. "Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Sagar Mahale & Meenakshi Setia & Bharat Prajapati & Santhilal Subhash & Mukesh Pratap Yadav & Subazini Thankaswamy Kosalai & Ananya Deshpande & Jagannath Kuchlyan & Mirco Di Marco & Fredrik Westerlund, 2022. "HnRNPK maintains single strand RNA through controlling double-strand RNA in mammalian cells," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    8. Riccardo Calandrelli & Xingzhao Wen & John Lalith Charles Richard & Zhifei Luo & Tri C. Nguyen & Chien-Ju Chen & Zhijie Qi & Shuanghong Xue & Weizhong Chen & Zhangming Yan & Weixin Wu & Kathia Zaleta-, 2023. "Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Simeon R. Mihaylov & Lydia M. Castelli & Ya-Hui Lin & Aytac Gül & Nikita Soni & Christopher Hastings & Helen R. Flynn & Oana Păun & Mark J. Dickman & Ambrosius P. Snijders & Robert Goldstone & Oliver, 2023. "The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    10. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33356-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.