Researchers from Wageningen University & Research and the Van Andel Institute have developed a high-precision CRISPR-based methodology that differentiates malignant cells from healthy tissue by exploiting epigenetic “fingerprints.” Published in Nature, the study introduces a novel application of ThermoCas9 a bacterial enzyme discovered by Dr. John van der Oost, which utilises DNA methylation patterns as a molecular addressing system to selectively target tumour DNA.
The biochemical basis of this selectivity lies in the enzyme’s interaction with the Protospacer Adjacent Motif (PAM). Structural analysis led by Dr. Hong Li revealed that ThermoCas9’s binding affinity is governed by the presence of methyl groups within the PAM sequence. In healthy cells, the methyl group acts as a physical protrusion that prevents the enzyme from seated correctly, akin to a screwdriver unable to fit into a blocked screw head. Because cancer cells exhibit altered methylation patterns, the enzyme can successfully bind and cleave tumour DNA while leaving healthy, methylated DNA intact.
While this study marks the first instance of a CRISPR system responding to the most abundant type of human DNA methylation, the authors characterise the findings as an early-stage proof-of-concept. Current results demonstrate successful DNA cleavage in human cell cultures but have not yet confirmed the induction of apoptosis. Future research will focus on maximising DNA damage to ensure therapeutic efficacy. Furthermore, this mechanism holds potential for treating other conditions defined by aberrant methylation, including autoimmune disorders and paediatric neuroblastoma.
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Article can be accessed on: Phys.org
Image Credit: Nature (2026).
