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

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• APOBEC3 cytidine deaminases are key drivers of cancer evolution.
• Targeting cancer cells with APOBEC3 activity presents a significant clinical challenge.

Purpose of the Study:

• To identify the DNA repair pathway for APOBEC3-induced double-strand breaks (DSBs).
• To investigate the therapeutic potential of inhibiting DNA polymerase theta (Polθ) in APOBEC3-active cancers.

Main Methods:

• Utilized fluorescent DSB repair reporters and a novel biochemical assay.
• Analyzed genomic data from clinical tumor samples.
• Performed in vitro and in vivo studies to assess synthetic lethality.

Main Results:

• Identified theta-mediated end joining (TMEJ) as the primary repair pathway for APOBEC3-induced DSBs.
• Demonstrated that APOBEC3A competes with RPA, exposing microhomology and favoring TMEJ.
• Confirmed cooccurrence of APOBEC3 mutational footprints, MMDs, and TMEJ signatures in tumors.
• Showed Polθ inhibition synergizes with APOBEC3A-induced DSBs to cause synthetic lethality.

Conclusions:

• TMEJ is the preferred repair mechanism for APOBEC3A-induced DSBs.
• Polθ inhibition is a promising strategy to eliminate cancer cells with APOBEC3A activity.