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APOBEC3A-Induced DNA Damage Drives Polymerase θ Dependency and Synthetic Lethality in Cancer
Abhishek Bose1, Weisi Liu1, Paul Yoo1
1Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
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) synergizes with APOBEC3A-induced DSBs to induce synthetic lethality in vitro and in vivo. Collectively, our findings identify TMEJ as the preferred mechanism for repairing APOBEC3A-induced DSBs and establish Polθ inhibition as a novel promising strategy to eliminate cancer cells with APOBEC3A activity.
Insights
APOBEC3 enzymes cause cancer mutations. Targeting these cancer cells is difficult, but inhibiting DNA polymerase theta (Polθ) offers a new strategy by exploiting APOBEC3-induced DNA damage.
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.
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