Journal
SCIENCE ADVANCES
Volume 6, Issue 25, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz4849
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Funding
- I&I Fund (Erasmus Vrienden Fonds)
- LSH-TKI foundation [LSHM18006]
- Ride for the Roses Cancer Research Grant from the Dutch Cancer Society
- Netherlands Organization of Scientific Research (NWO, TOP grant) [714.015.001]
- Department of Medical Microbiology and Infectious Diseases
- Department of Bioinformatics, Erasmus MC
- Oncode Institute - Dutch Cancer Society (KWF)
- Dutch Research Council (NWO)
- H2020 project ImmuneAID
- H2020 project Moodstratification
- ZonMW
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CRISPR-Cas9 systems are enriched in human pathogenic bacteria and have been linked to cytotoxicity by an unknown mechanism. Here, we show that upon infection of human cells, Campylobacter jejuni secretes its Cas9 (CjeCas9) nuclease into their cytoplasm. Next, a native nuclear localization signal enables CjeCas9 nuclear entry, where it catalyzes metal-dependent nonspecific DNA cleavage leading to cell death. Compared to CjeCas9, native Cas9 of Streptococcus pyogenes (SpyCas9) is more suitable for guide-dependent editing. However, in human cells, native SpyCas9 may still cause some DNA damage, most likely because of its ssDNA cleavage activity. This side effect can be completely prevented by saturation of SpyCas9 with an appropriate guide RNA, which is only partially effective for CjeCas9. We conclude that CjeCas9 plays an active role in attacking human cells rather than in viral defense. Moreover, these unique catalytic features may therefore make CjeCas9 less suitable for genome editing applications.
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