IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-62606-z.html
   My bibliography  Save this article

The hidden risks of CRISPR/Cas: structural variations and genome integrity

Author

Listed:
  • Clotilde Aussel

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg)

  • Toni Cathomen

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg
    Partner Site Freiburg
    University of Freiburg)

  • Carla Fuster-García

    (Medical Center – University of Freiburg
    Medical Center – University of Freiburg)

Abstract

CRISPR/Cas technology has revolutionized genome engineering, unlocking unprecedented therapeutic potential. However, beyond well-documented concerns of off-target (OT) mutagenesis, recent studies reveal a more pressing challenge: large structural variations (SVs), including chromosomal translocations and megabase-scale deletions, particularly in cells treated with DNA-PKcs inhibitors. These undervalued genomic alterations raise substantial safety concerns for clinical translation. As more CRISPR-based therapies progress toward the clinic, understanding and mitigating these risks is paramount. Here, we review emerging evidence on on-target aberrations and chromosomal translocations, identify key gaps in our understanding of the DNA repair pathways underlying these adverse effects, and discuss strategies to improve the safety of genome editing.

Suggested Citation

  • Clotilde Aussel & Toni Cathomen & Carla Fuster-García, 2025. "The hidden risks of CRISPR/Cas: structural variations and genome integrity," Nature Communications, Nature, vol. 16(1), pages 1-5, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62606-z
    DOI: 10.1038/s41467-025-62606-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-62606-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-62606-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. Sandra Wimberger & Nina Akrap & Mike Firth & Johan Brengdahl & Susanna Engberg & Marie K. Schwinn & Michael R. Slater & Anders Lundin & Pei-Pei Hsieh & Songyuan Li & Silvia Cerboni & Jonathan Sumner &, 2023. "Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Ron Baik & M. Kyle Cromer & Steve E. Glenn & Christopher A. Vakulskas & Kay O. Chmielewski & Amanda M. Dudek & William N. Feist & Julia Klermund & Suzette Shipp & Toni Cathomen & Daniel P. Dever & Mat, 2024. "Transient inhibition of 53BP1 increases the frequency of targeted integration in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Gregory A. Newby & Jonathan S. Yen & Kaitly J. Woodard & Thiyagaraj Mayuranathan & Cicera R. Lazzarotto & Yichao Li & Heather Sheppard-Tillman & Shaina N. Porter & Yu Yao & Kalin Mayberry & Kelcee A. , 2021. "Base editing of haematopoietic stem cells rescues sickle cell disease in mice," Nature, Nature, vol. 595(7866), pages 295-302, July.
    4. Grégoire Cullot & Julian Boutin & Jérôme Toutain & Florence Prat & Perrine Pennamen & Caroline Rooryck & Martin Teichmann & Emilie Rousseau & Isabelle Lamrissi-Garcia & Véronique Guyonnet-Duperat & Al, 2019. "CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    5. Killian S. Hanlon & Benjamin P. Kleinstiver & Sara P. Garcia & Mikołaj P. Zaborowski & Adrienn Volak & Stefan E. Spirig & Alissa Muller & Alexander A. Sousa & Shengdar Q. Tsai & Niclas E. Bengtsson & , 2019. "High levels of AAV vector integration into CRISPR-induced DNA breaks," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    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. Arianna Moiani & Gil Letort & Sabrina Lizot & Anne Chalumeau & Chloe Foray & Tristan Felix & Diane Clerre & Sonal Temburni-Blake & Patrick Hong & Sophie Leduc & Noemie Pinard & Alan Marechal & Eduardo, 2024. "Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Jianli Tao & Qi Wang & Carlos Mendez-Dorantes & Kathleen H. Burns & Roberto Chiarle, 2022. "Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Jianhang Yin & Kailun Fang & Yanxia Gao & Liqiong Ou & Shaopeng Yuan & Changchang Xin & Weiwei Wu & Wei-wei Wu & Jiaxu Hong & Hui Yang & Jiazhi Hu, 2022. "Safeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    4. Juan A. Perez-Bermejo & Oghene Efagene & William M. Matern & Jeffrey K. Holden & Shaheen Kabir & Glen M. Chew & Gaia Andreoletti & Eniola Catton & Craig L. Ennis & Angelica Garcia & Trevor L. Gerstenb, 2024. "Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Changchang Xin & Jianhang Yin & Shaopeng Yuan & Liqiong Ou & Mengzhu Liu & Weiwei Zhang & Jiazhi Hu, 2022. "Comprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Dmitrii Degtev & Jack Bravo & Aikaterini Emmanouilidi & Aleksandar Zdravković & Oi Kuan Choong & Julia Liz Touza & Niklas Selfjord & Isabel Weisheit & Margherita Francescatto & Pinar Akcakaya & Michel, 2024. "Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Sundaram Acharya & Asgar Hussain Ansari & Prosad Kumar Das & Seiichi Hirano & Meghali Aich & Riya Rauthan & Sudipta Mahato & Savitri Maddileti & Sajal Sarkar & Manoj Kumar & Rhythm Phutela & Sneha Gul, 2024. "PAM-flexible Engineered FnCas9 variants for robust and ultra-precise genome editing and diagnostics," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    9. Lisa Maria Riedmayr & Klara Sonnie Hinrichsmeyer & Stefan Bernhard Thalhammer & David Manuel Mittas & Nina Karguth & Dina Yehia Otify & Sybille Böhm & Valentin Johannes Weber & Michael David Bartosche, 2023. "mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. Lukas Möller & Eric J. Aird & Markus S. Schröder & Lena Kobel & Lucas Kissling & Lilly van de Venn & Jacob E. Corn, 2022. "Recursive Editing improves homology-directed repair through retargeting of undesired outcomes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    11. Raed Ibraheim & Phillip W. L. Tai & Aamir Mir & Nida Javeed & Jiaming Wang & Tomás C. Rodríguez & Suk Namkung & Samantha Nelson & Eraj Shafiq Khokhar & Esther Mintzer & Stacy Maitland & Zexiang Chen &, 2021. "Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    12. Xiangjun He & Zhenjie Zhang & Junyi Xue & Yaofeng Wang & Siqi Zhang & Junkang Wei & Chenzi Zhang & Jue Wang & Brian Anugerah Urip & Chun Christopher Ngan & Junjiang Sun & Yuefeng Li & Zhiqian Lu & Hui, 2022. "Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Milan Gautam & Antony Jozic & Grace Li-Na Su & Marco Herrera-Barrera & Allison Curtis & Sebastian Arrizabalaga & Wayne Tschetter & Renee C. Ryals & Gaurav Sahay, 2023. "Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Wei Qin & Fang Liang & Sheng-Jia Lin & Cassidy Petree & Kevin Huang & Yu Zhang & Lin Li & Pratishtha Varshney & Philippe Mourrain & Yanmei Liu & Gaurav K. Varshney, 2024. "ABE-ultramax for high-efficiency biallelic adenine base editing in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    15. G. Cullot & J. Boutin & S. Fayet & F. Prat & J. Rosier & D. Cappellen & I. Lamrissi & P. Pennamen & J. Bouron & S. Amintas & C. Thibault & I. Moranvillier & E. Laharanne & J. P. Merlio & V. Guyonnet-D, 2023. "Cell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    16. Emily Zhang & Monica E. Neugebauer & Nicholas A. Krasnow & David R. Liu, 2024. "Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. Burcu Bestas & Sandra Wimberger & Dmitrii Degtev & Alexandra Madsen & Antje K. Rottner & Fredrik Karlsson & Sergey Naumenko & Megan Callahan & Julia Liz Touza & Margherita Francescatto & Carl Ivar Möl, 2023. "A Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Mohsin Badat & Ayesha Ejaz & Peng Hua & Siobhan Rice & Weijiao Zhang & Lance D. Hentges & Christopher A. Fisher & Nicholas Denny & Ron Schwessinger & Nirmani Yasara & Noemi B. A. Roy & Fadi Issa & And, 2023. "Direct correction of haemoglobin E β-thalassaemia using base editors," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    19. Michael Kosicki & Felicity Allen & Frances Steward & Kärt Tomberg & Yangyang Pan & Allan Bradley, 2022. "Cas9-induced large deletions and small indels are controlled in a convergent fashion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    20. Ron Baik & M. Kyle Cromer & Steve E. Glenn & Christopher A. Vakulskas & Kay O. Chmielewski & Amanda M. Dudek & William N. Feist & Julia Klermund & Suzette Shipp & Toni Cathomen & Daniel P. Dever & Mat, 2024. "Transient inhibition of 53BP1 increases the frequency of targeted integration in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 15(1), pages 1-14, 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:16:y:2025:i:1:d:10.1038_s41467-025-62606-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.