️ Episode 118: Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B

In this episode of PaperCast Base by Base, we explore how cancer cells co-opt a primate-specific KRAB zinc finger protein, ZNF93, to fine-tune the mutagenic enzyme APOBEC3B and manage replication stress.

Study Highlights:
Using genome-wide KZFP binding maps, CUT&Tag, RNA-seq, and functional assays across multiple cancer cell lines, the authors identify ZNF93 as a proliferation-linked regulator enriched at promoters of young endonuclease-competent LINE-1 elements and as a direct repressor of APOBEC3B. ZNF93 knockdown consistently reduces proliferation, activates replication stress and DNA-damage checkpoints, and triggers inflammatory programs, while ZNF93 overexpression improves recovery from genotoxic insult similarly to APOBEC3B depletion. Mechanistically, ZNF93 binds the APOBEC3B promoter and suppresses its expression largely independent of TRIM28-mediated heterochromatin, with ZNF93 loss driving strong APOBEC3B upregulation and heightened stress signaling. Across human tumors, ZNF93 levels broadly correlate with proliferation and are elevated in many cancers, whereas HPV-positive cervical cancers show reduced ZNF93 alongside elevated APOBEC3B, suggesting tumors tune this axis to balance mutagenesis with tolerable replication stress.

Conclusion:
ZNF93 operates as a primate-specific rheostat that restrains APOBEC3B-driven replication stress and is exploited by tumors, highlighting a potential therapeutic lever to modulate genome instability in cancer.

Reference:
Forey R, Raclôt C, Pulver C, Rosspopoff O, Offner S, Duc J, Planet E, Martins F, Turelli P, Trono D. Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B. Proceedings of the National Academy of Sciences. 2025;122(34):e2505021122. https://doi.org/10.1073/pnas.2505021122

License:
This episode is based on an open-access article published under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) – https://creativecommons.org/licenses/by-nc-nd/4.0/

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Keywords: ZNF93; APOBEC3B; replication stress; KRAB zinc finger proteins; cancer epigenetics