Enterprise AI Analysis
APOBEC3C coordinates DDX5 in R-loop resolution and dynamic control of Chk1-mediated stress-responsive circuitry as a prerequisite for gemcitabine resistance in p53-deficient cells
This study identifies APOBEC3C (A3C) as a key factor in gemcitabine resistance in p53-deficient lung cancer cells. A3C promotes Chk1-dependent S-phase checkpoint activation, slowing replication fork progression and aiding DNA repair. Crucially, A3C interacts with RNA helicase DDX5 to coordinate R-loop resolution. Inhibition of DDX5 attenuates Chk1 activation and enhances gemcitabine's therapeutic effect by accumulating R-loops. The A3C/DDX5/R-loop complex modulates Chk1 dynamics and DNA replication/damage response, offering a novel target to overcome drug resistance in checkpoint-deficient tumors.
Key Enterprise Impact Metrics
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Increased Replication Stress Tolerance
A3C overexpression increased gemcitabine IC50 from 13.33µM to 249.6µM (48h).
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Improved DNA Repair Efficiency
A3C reduces chromosomal aberrations by 1500 segments upon gemcitabine treatment.
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Reduced R-Loop Accumulation
A3C and DDX5 jointly reduce gemcitabine-induced R-loop foci by 80%.
Deep Analysis & Enterprise Applications
Select a topic to dive deeper, then explore the specific findings from the research, rebuilt as interactive, enterprise-focused modules.
Enterprise Process Flow
Gemcitabine Induces Replication Stress
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A3C Upregulation in p53-deficient cells
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A3C Interacts with DDX5
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Coordinated R-loop Resolution
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Chk1-dependent S-phase Checkpoint Activation
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Enhanced DNA Repair & Replication Fork Stability
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Gemcitabine Resistance
This module illustrates the step-by-step mechanism by which APOBEC3C (A3C) and DDX5 collaborate to resolve R-loops, leading to gemcitabine resistance.
78%
Reduction in DNA Damage (53BP1 foci)
A3C's role in modulating Chk1 activity and mitigating DNA damage is central to its protective effect against gemcitabine.
| Feature | A3C-Proficient Cells | A3C-Deficient Cells |
|---|---|---|
| Gemcitabine IC50 (48h) | 249.6 µM | 13.33 µM |
| Chk1 Activation (p-Chk1) | Enhanced | Attenuated |
| R-loop Accumulation | Reduced | Increased |
| Gemcitabine + Chk1 Inhibitor Synergy | Impaired (CI values > 0.3) | Strong (CI values < 0.3) |
This table compares the cellular responses and drug interactions in A3C-proficient versus A3C-deficient cells, highlighting the impact of A3C on gemcitabine sensitivity.
A3C in Pancreatic Cancer Resistance
"Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma."
— Qian et al., Oncogenesis 2022
- A3C linked to mutational signature in pancreatic cancer.
- Facilitates gemcitabine resistance by resolving stalled replication forks.
- Suggests A3C/DDX5 pathway as a novel therapeutic target.
The study's findings have direct relevance to pancreatic cancer, where gemcitabine is a common treatment and A3C's role in resistance is emerging.
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