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

What is it about?

Our DNA is constantly threatened by internal forces, such as rogue genetic elements and enzymes capable of inducing mutations. While some mutations help cancer cells adapt and survive, excessive genotoxic stress can be lethal to them. To cope, cancer hijacks an epigenetic regulator found only in primates. Hidden within our genome are ancient viral-like sequences known as transposable elements. These sequences can copy and insert themselves into DNA, causing breaks and sometimes triggering inflammation. To prevent such damage, our cells rely on a family of DNA-binding proteins that keep these sequences under control. One of these proteins is ZNF93, which evolved to recognize and repress a specific group of repetitive DNA sequences. These sequences, called LINE-1, have mostly lost their ability to move around the genome, yet ZNF93 continues to bind them. Interestingly, cancer cells often produce more ZNF93 than their normal counterparts, although the reason remains unclear. A team led by Didier Trono at EPFL has now shown that cancer cells exploit ZNF93 to regulate APOBEC3B, a DNA-editing enzyme that drives mutations. APOBEC3B is a double-edged sword: it fuels tumor evolution but, if left unchecked, can damage DNA to the point of killing the cell. The study, conducted by Romain Forey and published in PNAS, demonstrates that tumors use ZNF93 to keep this enzyme in balance. The researchers found that ZNF93 levels rise in rapidly dividing cancer cells. When ZNF93 was inhibited across different cancer types, cell growth slowed, and signs of DNA damage and inflammation appeared. Initially, the team suspected this was due to the loss of LINE-1 control. However, they discovered that related proteins had compensated for LINE-1 regulation. Instead, they observed a sharp increase in APOBEC3B, which is directly repressed by ZNF93. By moderating APOBEC3B levels, ZNF93 shields cancer cells from the harmful effects of unchecked mutation. In fact, the scientists showed that when ZNF93 levels were boosted, cells recovered more quickly from stress—a finding that may explain why many tumors exhibit high ZNF93 expression.

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Why is it important?

This study uncovers a surprising strategy cancer cells use to balance mutation with survival. By co-opting a primate-specific regulatory system, tumors can fine-tune a mutagenic enzyme that is both beneficial and dangerous. Understanding this feedback loop could open new avenues for targeting cancers that rely on it.

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