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Updated: Jan 1, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Cell Death Response to DNA Damage
1Department of Cellular & Molecular Medicine, University of California, San Diego, CA.
Abstract:
The cell death response to DNA damage is discussed in this Perspectives piece with cancer as the backdrop because DNA damaging agents (DDA) are widely used to treat cancer. From decades of clinical results, we learn that DDA have cured some cancers but their toxicity is temporary in most cancers due to emergence of DDA-resistant cancer cells. Investigation of DDA-activated genes, proteins, and pathways, known collectively as the DNA damage response (DDR), has uncovered the inner workings of DDR that protect the genome to sustain life. Paradoxically, however, DDR can also activate death. Current knowledge on DDA-activated death and hypotheses for how DDR may determine when and where to execute death are discussed. Given that cancer cells suffer from DDR defects, which account for their initial sensitivity to DDA, future therapeutic development may exploit those cancer-specific DDR defects to selectively create death-inducing DNA lesions, without using DDA, to kill DDA-resistant cancers.
Insights
DNA damaging agents (DDA) treat cancer but resistance emerges. The DNA damage response (DDR) can both protect cells and trigger death, offering new therapeutic strategies against resistant cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- DNA damaging agents (DDA) are crucial in cancer therapy, yet their efficacy is limited by the development of DDA-resistant cancer cells.
- The DNA damage response (DDR) network comprises genes, proteins, and pathways that protect the genome but can paradoxically induce cell death.
Purpose of the Study:
- To review the dual role of DDR in protecting the genome and initiating cell death.
- To explore how DDR determines the timing and location of cell death execution.
- To discuss exploiting cancer-specific DDR defects for novel therapeutic strategies.
Main Methods:
- Review of existing literature on DDA and DDR mechanisms.
- Analysis of clinical outcomes from DDA cancer treatments.
- Hypothesizing DDR's role in cell death regulation.
Main Results:
- DDA can cure some cancers, but resistance frequently develops due to DDR.
- DDR activation can lead to either genome protection or programmed cell death.
- Cancer cells often possess DDR defects, contributing to initial DDA sensitivity.
Conclusions:
- Understanding DDR's complex role in cell death is critical for cancer therapy.
- Targeting cancer-specific DDR defects presents a promising avenue for overcoming DDA resistance.
- Future therapies may involve inducing death-inducing DNA lesions without DDA to eliminate resistant tumors.
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