Scientists Report First Chemical Probes That Block CDCA7’s DNA Recognition

Researchers report the first chemical probes that target CDCA7, a protein that reads hemi-methylated DNA and helps maintain methylation patterns across the genome. Writing in Biological Research, the team describes how structure-guided virtual screening, followed by biochemical and cellular validation, identified two structurally distinct compounds that selectively interfere with CDCA7’s binding to hemi-methylated DNA while showing minimal activity toward CDCA7L, a closely related paralog.

CDCA7 functions within the ZBTB24–CDCA7–HELLS pathway, which promotes the maintenance of DNA methylation in heterochromatic regions. Maintenance of DNA methylation is essential for genome stability and epigenetic inheritance, and while the enzymatic machinery behind this process has been extensively characterized, whether the regulatory proteins governing it can be chemically modulated had remained largely unexplored. Dysfunction of CDCA7 is known to cause Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome, making the protein a protein of considerable biological and medical interest.

In the new study, the two compounds disrupted CDCA7–DNA interactions in vitro, impaired antibody class switch recombination in B cells, and induced hypomethylation of pericentromeric satellite repeats. According to the authors, these effects partially recapitulate key molecular and cellular phenotypes associated with CDCA7 deficiency, indicating that the compounds engage the expected biological pathway rather than acting as indiscriminate DNA-binding inhibitors.

The work establishes CDCA7-mediated DNA recognition as a chemically tractable biological process and provides the first chemical probes for investigating the functions of the ZBTB24–CDCA7–HELLS pathway and non-canonical DNA methylation maintenance. As probes rather than drugs, the compounds are intended as research tools to dissect how this pathway sustains heterochromatic methylation, and the authors note that the findings open a route to studying regulatory proteins in DNA methylation maintenance that had previously been inaccessible to chemical modulation.

Subject of Research: Discovery of chemical probes targeting CDCA7-mediated hemi-methylated DNA recognition in the ZBTB24–CDCA7–HELLS pathway

Article Title: Structure-guided discovery of chemical probes targeting CDCA7-mediated DNA recognition

Article References: Liu, C., Zhao, Z., Yang, C., Zheng, G., He, R., Xiao, Z., & Ying, Z. (2026). Structure-guided discovery of chemical probes targeting CDCA7-mediated DNA recognition. Biological Research. https://doi.org/10.1186/s40659-026-00735-5

Image Credits: AI Generated

DOI: 10.1186/s40659-026-00735-5

Keywords: CDCA7, chemical probes, DNA methylation, epigenetics, ICF syndrome, virtual screening, ZBTB24–CDCA7–HELLS, heterochromatin, B cells, hypomethylation, Structure-guided, discovery