One Enzyme Likely Responsible for Mutations in Most Cancers

Good news! Cancer is history (soon)!

"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. ...
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,” ..."

From the abstract:

"The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures."

Underdog Enzyme Likely Responsible for Mutations in Most Cancers | The Scientist Magazine® A previously overlooked enzyme called APOBEC3A is linked to the most prevalent mutational signatures in cancer cell lines, a study finds.

Mechanisms of APOBEC3 mutagenesis in human cancer cells (open access)

Fig. 4: APOBEC3 deaminases drive the acquisition of clustered mutations in human cancer cells