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

Romain Forey; Charlène Raclot; Cyril Pulver; Olga Rosspopoff; Sandra Eloise Offner; Julien Duc; Evarist Planet; Filipe Martins; Priscilla Turelli; Didier Trono

doi:10.1073/pnas.2505021122

GeneticsProceedings of the National Academy of SciencesAug 19, 2025

Peer-reviewed journal article

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

Romain Forey iD, Charlène Raclot iD, Cyril Pulver iD, Olga Rosspopoff iD, Sandra Eloise Offner iD, Julien Duc iD, Evarist Planet iD, Filipe Martins iD, Priscilla Turelli iD, Didier Trono iD

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Abstract

ZNF93 is a primate-restricted KRAB zinc finger protein responsible for repressing 20- to 12-million-year-old L1 transposable elements. Here, we reveal that ZNF93 also regulates the key cancer driver APOBEC3B--a mutagenic enzyme linked to tumorigenesis and cancer progression. ZNF93 depletion impairs DNA synthesis, activates replication and DNA damage checkpoints, and triggers proinflammatory phenotypes. Conversely, its overexpression enhances resistance to exogenous genotoxic stress, mirroring the effects observed with APOBEC3B depletion. ZNF93 expression correlates with cell proliferation rates and is overexpressed in many cancer types. These findings suggest that ZNF93 serves as a critical guardian of genome integrity, co-opted by cancer cells to counterbalance APOBEC3B-induced and L1-derived genomic instability and inflammation.