APOBEC3A-Induced DNA Damage Drives Polymerase θ Dependency and Synthetic Lethality in Cancer.

ABSTRACT: APOBEC3 cytidine deaminases drive cancer evolution. There is an unmet need to target cancer cells with APOBEC3 activity. Here, we identify error-prone theta-mediated end joining (TMEJ) as the main pathway for repairing APOBEC3-induced double-strand breaks (DSBs). Using fluorescent DSB repair reporters and a novel biochemical assay, we demonstrate that APOBEC3A competes with replication protein A (RPA) for single-stranded DNA overhangs, exposing microhomologous sequences to shift DSB repair towards error-prone TMEJ. Genomic analysis of clinical tumor samples confirmed the cooccurrence and proximity between APOBEC3-induced mutational footprints, microhomology-mediated deletions (MMDs), and TMEJ-associated chromosomal instability signatures. Crucially, inhibition of DNA polymerase theta (Polθ

SUBMITTER: Bose A 

PROVIDER: S-EPMC12633405 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature