How cancer exploits a primate protein to control DNA stress

Our DNA is constantly under threat from internal forces like rogue genetic elements and enzymes that can mutate it. While some mutations help cancer cells adapt and survive, too much genotoxic stress can kill them. To manage this, cancer subvert an epigenetic modulator found only in primates.

Hidden in our genome are ancient, viral-like sequences called transposable elements. These sequences can copy and insert themselves into DNA, creating breaks and sometimes triggering inflammation. To prevent damage, our cells use a family of DNA-binding proteins to keep them in check.

One of them is ZNF93, which evolved to recognize and repress a specific group of repetitive DNA sequences. These sequences, known as LINE-1, have mostly lost their ability to move around the genome, but ZNF93 still binds to them. Interestingly, cancer cells often produce more of this protein than their normal counterpart, though it wasn’t clear why.

The group of Didier Trono at EPFL has now shown that cancer cells exploit ZNF93 to control APOBEC3B, a DNA-editing enzyme that promotes mutations. APOBEC3B is a double-edged sword: it helps tumors evolve but, when uncontrolled, causes DNA damage that can kill the cell. The study, led by Romain Forey and published in PNAS, shows that tumors use ZNF93 to keep this enzyme in balance.

The researchers found that ZNF93 levels rise in fast-dividing cancer cells. Silencing it in different cancer cell types slowed their growth and triggered signs of DNA damage and inflammation. While the researchers supposed that this was due to loss of control of LINE-1, they found that it was not the case, probably because ZNF93 relatives took the job over. Instead, they observed a sharp increase in APOBEC3B, the DNA-editing enzyme, which they demonstrated is a direct target of ZNF93-mediated shutdown.

By moderating APOBEC3B levels, ZNF93 protects cancer cells from the damaging effects of uncontrolled mutation. In fact, the scientists found that when ZNF93 levels were increased, cells recovered more quickly from stress, possibly explaining why so many tumors show high ZNF93 levels.

The study uncovers a surprising trick cancer cells use to manage the balance between mutation and survival. By borrowing a primate-specific control system, tumors can fine-tune a mutagenic enzyme that both helps and threatens them. Understanding this regulatory loop could lead to new ways of targeting cancers that rely on it. It also shows how even recently evolved genes can end up playing critical roles in fundamental processes like DNA replication and repair.

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