Isoform-specific characterization implicates alternative splicing inAPOBEC3Bas a mechanism restricting APOBEC-mediated mutagenesis

Abstract

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis, but the understanding of the regulation of their mutagenic activity remains limited. Here, we showed that mutagenic and non-mutagenic A3A and A3B enzymes are produced by canonical and alternatively spliced A3A and A3B isoforms, respectively. Notably, increased expression of the canonical A3B isoform, which encodes the mutagenic A3B enzyme, predicted shorter progression-free survival of bladder cancer patients. Expression of the mutagenic A3B isoform was reduced by exon 5 skipping, generating a non-mutagenic A3B isoform. The exon 5 skipping, which was dependent on the interaction between SF3B1 splicing factor and weak branch point sites in intron 4, could be enhanced by an SF3B1 inhibitor, decreasing the production of the mutagenic A3B enzyme. Thus, our results underscore the role of A3B, especially in bladder cancer, and implicate alternative splicing of A3B as a mechanism and therapeutic target to restrict APOBEC-mediated mutagenesis.

APOBECs orchestrate genomic and epigenomic editing across health and disease

“…Moreover, alternative splicing can also control APOBEC function through the generation of isoforms (e.g., A3A, B, H, and F). A3B splice variants can restrain mutagenic A3B1 expression [36]. A3H function can be diversified by alternative splicing into three isoforms: non-functional, maintained function, and enhanced viral restriction function [37].…”