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

• 成果类型: Article
• 署名作者: Forey, Romain; Raclot, Charlene; Pulver, Cyril; Rosspopoff, Olga; Offner, Sandra; Duc, Julien; Planet, Evarist; Martins, Filipe; Turelli, Priscilla; Trono, Didier
• 署名单位: Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss School of Public Health (SSPH+)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13770
• DOI: 10.1073/pnas.2505021122
• 发表日期: 2025-08-26
• 关键词: line-1 retrotransposition; interferon response; replication stress; dna; mutagenesis; EVOLUTION; drives

摘要

ZNF93 is a primate-restricted Kr & uuml;ppel-associated box zinc finger protein responsible for repressing 20-to 12-My-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.