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Cancer cells subvert ZNF93 to escape surveillance by L1 epigenetic sentinels and control APOBEC3B [RNA-seq_1]

GSE290770 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/08/01 Platform GPL20301
Summary
The primate-restricted KRAB zinc finger protein (KZFP) ZNF93 represses a subset of L1 transposable elements (TEs) that propagated in the human ancestral genome some 20 to 12 million years ago and have all become transposition-incompetent due to inactivating mutations. Here, we demonstrate that these L1 integrants encode a highly genotoxic endonuclease, and that ZNF93 also represses other full-length L1 integrants via indirect effects as well as APOBEC3B. Consistent with the exquisite sensitivity of single-stranded DNA to attack by both the L1 endonuclease and the cytidine deaminase, ZNF93 expression peaks in S phase and correlates with cell proliferation. ZNF93 is induced in most cancers, and ZNF93-depleted cells exhibit defects in DNA synthesis and activation of the replication and DNA damage checkpoints. These results suggest a model whereby ZNF93 is a major guardian of genome integrity subverted by cancer cells to escape L1-mediated epigenetic surveillance and achieve a proper balance of APOBEC3B-induced tumor heterogeneity and overall genome stability.
Published in
Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B
Forey R, Raclot C, Pulver C et al. · Proceedings of the National Academy of Sciences of the United States of America 2025 · PMID 40828019 · doi:10.1073/pnas.2505021122
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Also filed as BioProject PRJNA1230087 and SRA study SRP567030. Searching any of these in the dataset finder brings you back here.

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