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Artist’s 3D rendering of malignant cancer cells, illustrated in pink, as it would appear under a scanning electron microscope.
Artist’s 3D rendering of malignant cancer cells, illustrated in pink, as it would appear under a scanning electron microscope.

Underdog Enzyme Likely Responsible for Mutations in Most Cancers

A previously overlooked enzyme called APOBEC3A is linked to the most prevalent mutational signatures in cancer cell lines, a study finds.

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Sophie Fessl

Sophie Fessl is a freelance science journalist. She has a PhD in developmental neurobiology from King’s College London and a degree in biology from the University of Oxford.

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Over half of all the cancer genomes that researchers have sequenced share one characteristic: They contain mutational signatures associated with a family of enzymes called APOBEC3, suggesting a role for these enzymes in mutagenesis. So far, limited evidence suggests that the main culprit within the APOBEC3 family is the enzyme APOBEC3B. Though much about the enzyme’s activity remains unknown, the field largely focused on it as the primary enzyme responsible for cancer mutations. But APOBEC3A—previously thought not to play such a prominent role—may actually be responsible for the mutations seen in most cancer cell lines, a paper published July 20 in Nature suggests, making it a potential therapeutic target in cancer. 

Dmitry Gordenin, a specialist in APOBEC3 mutagenesis at the National Institute of Environmental Health Sciences who was not involved in the paper, says that the “excellent scientific work” shows that “most of the APOBEC3 mutations [in tumors] come from APOBEC3A.”

APOBEC3 enzymes’ main role is to induce mutations in viral RNA and DNA that stop pathogenic viruses from replicating. However, APOBEC3 enzymes have also been implicated in cancer, as some of the patterns of mutations discovered in human cancer genomes, called ‘mutational signatures’, were found to resemble mutational patterns that some APOBEC3 enzymes induce on viral nucleic acids. And this applies to more than just a few cancers: The mutational signatures associated with APOBEC activities, in particular that of the APOBEC3 subfamily, have been found “in more than 50 percent of all cancer genomes looked at up to date and more than 70 percent of cancer types,” says study coauthor Mia Petljak, a cancer genomicist at the Broad Institute of MIT and Harvard. 

Before the new study, however, there was no direct evidence that APOBEC3 enzymes are the cause of these mutational signatures, Petljak adds in an email to The Scientist. “In the absence of the causal link, contributions of individual APOBEC3 enzymes to mutations in cancer remained widely debated.” What the field was lacking before, Petljak explains, were human cancer cell models that acquire the APOBEC mutational signatures that would make it possible to study the effects of deleting APOBEC enzymes. Previously, indirect readouts such as the expression levels of APOBEC3 enzymes in different cancers, were used to get a glimpse at which APOBEC3 enzyme plays a more prominent role in cancer. Because APOBEC3B is often expressed at higher levels in cancer cells, researchers believed that it was the prime culprit.

See “Q&A: Nearly Every Single Human Gene Can Be Linked to Cancer

Petljak and coauthors made use of exactly the sort of models that had been missing from the literature, which they had initially presented in a 2019 study: human cancer cell lines that continuously generate APOBEC3 mutation signatures, even when cultivated, and specifically do so in a pattern that reflects what happens in cancer. Knocking out APOBEC3A, APOBEC3B, or both from these cell lines revealed that in most cases, APOBEC3A is the primary mutational enzyme. “When we knock out APOBEC3A, we diminish acquisition of the majority of these mutational signatures,” says Petljak. This was the first evidence that endogenous APOBEC enzymes cause the relevant mutational signatures in cancers, she adds. 

“In examined cell lines, specific mutational signatures that are diminished upon knocking out APOBEC3A are also the most prevalent type of APOBEC-associated signatures, so we think, and the evidence is strong, that APOBEC3A represents the predominant source of these signatures in [a] majority of cancer types,” Petljak writes in the email.

Not to be overshadowed, however, APOBEC3B still contributes to the mutational burden. In some cell lines, deletion of APOBEC3B surprisingly resulted in increased mutagenesis by APOBEC3A, although the mechanism behind this remains unclear.

This is important, says Petljak, as indirect evidence previously pointed towards APOBEC3B as the more prominent mutator in cancer, and because of that, APOBEC3B is currently being considered as a therapeutic target in cancer. 

Gordenin, however, points out that “there is no direct link between the level of mutagenesis in tumors and tumorigenesis or prognosis” and most mutations are just passengers—suggesting that APOBEC3 mutations may not affect cancer outcomes. However, Gordenin does agree that, given limited resources, the paper calls into question whether the current therapeutic focus on APOBEC3B is justified. In the future, Petljak plans to investigate what drives the activity of APOBEC3A in cancers, trying to identify the cell-intrinsic and environmental factors that trigger mutagenesis.

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