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Related Concept Videos

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Genome editing technologies allow scientists to modify an organism’s DNA via the addition, removal, or rearrangement of genetic material at specific genomic locations. These types of techniques could potentially be used to cure genetic disorders such as hemophilia and sickle cell anemia. One popular and widely used DNA-editing research tool that could lead to safe and effective cures for genetic disorders is the CRISPR-Cas9 system. CRISPR-Cas9 stands for Clustered Regularly Interspaced...
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Updated: Jan 25, 2026

Using Sniper-Cas9 to Minimize Off-target Effects of CRISPR-Cas9 Without the Loss of On-target Activity Via Directed Evolution
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Deciphering Off-Target Effects in CRISPR-Cas9 through Accelerated Molecular Dynamics.

Clarisse G Ricci1, Janice S Chen2, Yinglong Miao3

  • 1Department of Pharmacology, Department of Chemistry and Biochemistry, and National Biomedical Computation Resource, University of California San Diego, La Jolla, California 92093, United States.

ACS Central Science
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CRISPR-Cas9 off-target mutations are caused by DNA mismatches that fail to "lock" the HNH domain. This research clarifies the mechanism, paving the way for more specific gene-editing tools.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • CRISPR-Cas9 is a powerful tool for nucleic acid manipulation.
  • Off-target mutations limit the precision and applicability of CRISPR-Cas9 technology.

Purpose of the Study:

  • To elucidate the molecular mechanism behind CRISPR-Cas9 off-target binding and DNA cleavage.
  • To identify the structural factors that determine the specificity of Cas9 activity.

Main Methods:

  • All-atom enhanced molecular dynamics (MD) simulations using Gaussian accelerated MD (GaMD).
  • Analysis of RNA:DNA heteroduplex opening and interactions with the Cas9 HNH domain.

Main Results:

  • DNA mismatches at PAM-distal sites can prevent the formation of a "lock" interaction between DNA and the Cas9 HNH domain.
  • This "locking" mechanism is crucial for maintaining the inactive state of the HNH domain and preventing cleavage.
  • Failure to "lock" the HNH domain leads to unselective DNA cleavage and off-target effects.

Conclusions:

  • The ability of DNA mismatches to "lock" the HNH domain is a key determinant of CRISPR-Cas9 off-target effects.
  • Understanding this mechanism provides a basis for designing more specific Cas9 variants.
  • Strategies to enhance "locking" interactions could minimize undesired DNA cleavage by CRISPR-Cas9.