The APOBEC3A deaminase drives episodic mutagenesis in cancer cells

The APOBEC3 family of cytidine deaminases is widely speculated to be a major source of somatic mutations in cancer[1][1]–[3][2]. However, causal links between APOBEC3 enzymes and mutations in human cancer cells have not been established. The identity of the APOBEC3 paralog(s) that may act as prime drivers of mutagenesis and the mechanisms underlying different APOBEC3-associated mutational signatures are unknown. To directly investigate the roles of APOBEC3 enzymes in cancer mutagenesis, candidate APOBEC3 genes were deleted from cancer cell lines recently found to naturally generate APOBEC3-associated mutations in episodic bursts[4][3]. Deletion of the APOBEC3A paralog severely diminished the acquisition of mutations of speculative APOBEC3 origins in breast cancer and lymphoma cell lines. APOBEC3 mutational burdens were undiminished in APOBEC3B knockout cell lines. APOBEC3A deletion reduced the appearance of the clustered mutation types kataegis and omikli , which are frequently found in cancer genomes. The uracil glycosylase UNG and the translesion polymerase REV1 were found to play critical roles in the generation of mutations induced by APOBEC3A. These data represent the first evidence for a long-postulated hypothesis that APOBEC3 deaminases generate prevalent clustered and non-clustered mutational signatures in human cancer cells, identify APOBEC3A as a driver of episodic mutational bursts, and dissect the roles of the relevant enzymes in generating the associated mutations in breast cancer and B cell lymphoma cell lines. ### Competing Interest Statement M.P. is a shareholder in Vertex Pharmaceuticals. J.M. has received consulting fees from Ono Pharmaceutical Co. His spouse is an employee of and has equity in Bristol Myers Squibb. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4