IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43633-0.html
   My bibliography  Save this article

Dissecting the basis for differential substrate specificity of ADAR1 and ADAR2

Author

Listed:
  • Marlon S. Zambrano-Mila

    (Weizmann Institute of Science)

  • Monika Witzenberger

    (Weizmann Institute of Science)

  • Zohar Rosenwasser

    (Bar Ilan University)

  • Anna Uzonyi

    (Weizmann Institute of Science)

  • Ronit Nir

    (Weizmann Institute of Science)

  • Shay Ben-Aroya

    (Bar Ilan University)

  • Erez Y. Levanon

    (Bar Ilan University)

  • Schraga Schwartz

    (Weizmann Institute of Science)

Abstract

Millions of adenosines are deaminated throughout the transcriptome by ADAR1 and/or ADAR2 at varying levels, raising the question of what are the determinants guiding substrate specificity and how these differ between the two enzymes. We monitor how secondary structure modulates ADAR2 vs ADAR1 substrate selectivity, on the basis of systematic probing of thousands of synthetic sequences transfected into cell lines expressing exclusively ADAR1 or ADAR2. Both enzymes induce symmetric, strand-specific editing, yet with distinct offsets with respect to structural disruptions: −26 nt for ADAR2 and −35 nt for ADAR1. We unravel the basis for these differences in offsets through mutants, domain-swaps, and ADAR homologs, and find it to be encoded by the differential RNA binding domain (RBD) architecture. Finally, we demonstrate that this offset-enhanced editing can allow an improved design of ADAR2-recruiting therapeutics, with proof-of-concept experiments demonstrating increased on-target and potentially decreased off-target editing.

Suggested Citation

  • Marlon S. Zambrano-Mila & Monika Witzenberger & Zohar Rosenwasser & Anna Uzonyi & Ronit Nir & Shay Ben-Aroya & Erez Y. Levanon & Schraga Schwartz, 2023. "Dissecting the basis for differential substrate specificity of ADAR1 and ADAR2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43633-0
    DOI: 10.1038/s41467-023-43633-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43633-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-43633-0?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. Colleen M. Burns & Hsin Chu & Susan M. Rueter & Linda K. Hutchinson & Hervé Canton & Elaine Sanders-Bush & Ronald B. Emeson, 1997. "Regulation of serotonin-2C receptor G-protein coupling by RNA editing," Nature, Nature, vol. 387(6630), pages 303-308, May.
    2. Orshay Gabay & Yoav Shoshan & Eli Kopel & Udi Ben-Zvi & Tomer D. Mann & Noam Bressler & Roni Cohen‐Fultheim & Amos A. Schaffer & Shalom Hillel Roth & Ziv Tzur & Erez Y. Levanon & Eli Eisenberg, 2022. "Landscape of adenosine-to-inosine RNA recoding across human tissues," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Leila E. Rieder & Cynthia J. Staber & Barry Hoopengardner & Robert A. Reenan, 2013. "Tertiary structural elements determine the extent and specificity of messenger RNA editing," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    4. Jeffrey J. Ishizuka & Robert T. Manguso & Collins K. Cheruiyot & Kevin Bi & Arpit Panda & Arvin Iracheta-Vellve & Brian C. Miller & Peter P. Du & Kathleen B. Yates & Juan Dubrot & Ilana Buchumenski & , 2019. "Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade," Nature, Nature, vol. 565(7737), pages 43-48, January.
    5. Nicholas W. Hubbard & Joshua M. Ames & Megan Maurano & Lan H. Chu & Kim Y. Somfleth & Nandan S. Gokhale & Margo Werner & Jessica M. Snyder & Katrina Lichauco & Ram Savan & Daniel B. Stetson & Andrew O, 2022. "ADAR1 mutation causes ZBP1-dependent immunopathology," Nature, Nature, vol. 607(7920), pages 769-775, July.
    6. Hagit T. Porath & Shai Carmi & Erez Y. Levanon, 2014. "A genome-wide map of hyper-edited RNA reveals numerous new sites," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    7. Robert A. Reenan, 2005. "Molecular determinants and guided evolution of species-specific RNA editing," Nature, Nature, vol. 434(7031), pages 409-413, March.
    8. Richard Reuver & Simon Verdonck & Evelien Dierick & Josephine Nemegeer & Eline Hessmann & Sadeem Ahmad & Maude Jans & Gillian Blancke & Filip Nieuwerburgh & Alexander Botzki & Lars Vereecke & Geert Lo, 2022. "ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation," Nature, Nature, vol. 607(7920), pages 784-789, July.
    9. Huipeng Jiao & Laurens Wachsmuth & Simone Wolf & Juliane Lohmann & Masahiro Nagata & Göksu Gökberk Kaya & Nikos Oikonomou & Vangelis Kondylis & Manuel Rogg & Martin Diebold & Simon E. Tröder & Branko , 2022. "ADAR1 averts fatal type I interferon induction by ZBP1," Nature, Nature, vol. 607(7920), pages 776-783, July.
    10. Meng How Tan & Qin Li & Raghuvaran Shanmugam & Robert Piskol & Jennefer Kohler & Amy N. Young & Kaiwen Ivy Liu & Rui Zhang & Gokul Ramaswami & Kentaro Ariyoshi & Ankita Gupte & Liam P. Keegan & Cyril , 2017. "Dynamic landscape and regulation of RNA editing in mammals," Nature, Nature, vol. 550(7675), pages 249-254, October.
    11. Julie M. Eggington & Tom Greene & Brenda L. Bass, 2011. "Predicting sites of ADAR editing in double-stranded RNA," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    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. Amir Dailamy & Weiqi Lyu & Sami Nourreddine & Michael Tong & Joseph Rainaldi & Daniella McDonald & Rebecca Panwala & Alysson Muotri & Michael S. Breen & Kun Zhang & Prashant Mali, 2024. "Charting and probing the activity of ADARs in human development and cell-fate specification," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Orshay Gabay & Yoav Shoshan & Eli Kopel & Udi Ben-Zvi & Tomer D. Mann & Noam Bressler & Roni Cohen‐Fultheim & Amos A. Schaffer & Shalom Hillel Roth & Ziv Tzur & Erez Y. Levanon & Eli Eisenberg, 2022. "Landscape of adenosine-to-inosine RNA recoding across human tissues," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Karthika Devi Kiran Kumar & Shubhangi Singh & Stella Maria Schmelzle & Paul Vogel & Carolin Fruhner & Alfred Hanswillemenke & Adrian Brun & Jacqueline Wettengel & Yvonne Füll & Lukas Funk & Valentin M, 2024. "An improved SNAP-ADAR tool enables efficient RNA base editing to interfere with post-translational protein modification," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Shuo Wang & An Song & Jun Xie & Yuan-Yuan Wang & Wen-Da Wang & Meng-Jie Zhang & Zhi-Zhong Wu & Qi-Chao Yang & Hao Li & Junjie Zhang & Zhi-Jun Sun, 2024. "Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Suba Rajendren & Xiang Ye & William Dunker & Antiana Richardson & John Karijolich, 2023. "The cellular and KSHV A-to-I RNA editome in primary effusion lymphoma and its role in the viral lifecycle," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Yiyi Ma & Eric B. Dammer & Daniel Felsky & Duc M. Duong & Hans-Ulrich Klein & Charles C. White & Maotian Zhou & Benjamin A. Logsdon & Cristin McCabe & Jishu Xu & Minghui Wang & Thomas S. Wingo & James, 2021. "Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    7. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    8. Gaia Rizzo & Mattia Veronese & Paul Expert & Federico E Turkheimer & Alessandra Bertoldo, 2016. "MENGA: A New Comprehensive Tool for the Integration of Neuroimaging Data and the Allen Human Brain Transcriptome Atlas," PLOS ONE, Public Library of Science, vol. 11(2), pages 1-20, February.
    9. Liran Carmel & Eugene V Koonin & Stella Dracheva, 2012. "Dependencies among Editing Sites in Serotonin 2C Receptor mRNA," PLOS Computational Biology, Public Library of Science, vol. 8(9), pages 1-13, September.
    10. Winston H. Cuddleston & Junhao Li & Xuanjia Fan & Alexey Kozenkov & Matthew Lalli & Shahrukh Khalique & Stella Dracheva & Eran A. Mukamel & Michael S. Breen, 2022. "Cellular and genetic drivers of RNA editing variation in the human brain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Caroline B. Albertin & Sofia Medina-Ruiz & Therese Mitros & Hannah Schmidbaur & Gustavo Sanchez & Z. Yan Wang & Jane Grimwood & Joshua J. C. Rosenthal & Clifton W. Ragsdale & Oleg Simakov & Daniel S. , 2022. "Genome and transcriptome mechanisms driving cephalopod evolution," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. You Wu & Wenna Shao & Mengxiao Yan & Yuqin Wang & Pengfei Xu & Guoqiang Huang & Xiaofei Li & Brian D. Gregory & Jun Yang & Hongxia Wang & Xiang Yu, 2024. "Transfer learning enables identification of multiple types of RNA modifications using nanopore direct RNA sequencing," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Lei Zhang & Li Jiang & Liang Yu & Qin Li & Xiangjun Tian & Jingquan He & Ling Zeng & Yuqin Yang & Chaoran Wang & Yuhan Wei & Xiaoyue Jiang & Jing Li & Xiaolu Ge & Qisheng Gu & Jikun Li & Di Wu & Antho, 2022. "Inhibition of UBA6 by inosine augments tumour immunogenicity and responses," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    16. Yuta Noda & Shunpei Okada & Tsutomu Suzuki, 2022. "Regulation of A-to-I RNA editing and stop codon recoding to control selenoprotein expression during skeletal myogenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    17. Jianheng Liu & Tao Huang & Wanying Chen & Chenhui Ding & Tianxuan Zhao & Xueni Zhao & Bing Cai & Yusen Zhang & Song Li & Ling Zhang & Maoguang Xue & Xiuju He & Wanzhong Ge & Canquan Zhou & Yanwen Xu &, 2022. "Developmental mRNA m5C landscape and regulatory innovations of massive m5C modification of maternal mRNAs in animals," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    18. Yazhong Cui & Yang Miao & Longzhi Cao & Lifang Guo & Yue Cui & Chuanzhe Yan & Zhi Zeng & Mo Xu & Ting Han, 2023. "Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, 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:14:y:2023:i:1:d:10.1038_s41467-023-43633-0. 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.