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Updated: Mar 6, 2026
Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited
Erkin Erdal1, Syed Haider1, Jan Rehwinkel2
1Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Abstract:
Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that antiviral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumors. Classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells can initiate type I IFN signaling. Here, we demonstrate that DNA-damaging modalities used during cancer therapy lead to the release of ssDNA fragments from the cell nucleus into the cytosol, engaging this innate immune response. We found that the factors that control DNA end resection during double-strand break repair, including the Bloom syndrome (BLM) helicase and exonuclease 1 (EXO1), play a major role in generating these DNA fragments and that the cytoplasmic 3'-5' exonuclease Trex1 is required for their degradation. Analysis of mRNA expression profiles in breast tumors demonstrates that those with lower Trex1 and higher BLM and EXO1 expression levels are associated with poor prognosis. Targeting BLM and EXO1 could therefore represent a novel approach for circumventing the IRDS produced in response to cancer therapeutics.
Insights
Cancer treatments like radiotherapy and chemotherapy can trigger type I interferon (IFN) signaling, leading to resistance. DNA damage during therapy releases nuclear DNA fragments, activating this immune response and impacting treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Radiotherapy and chemotherapy are standard cancer treatments but often encounter resistance.
- Type I interferon (IFN) signaling is induced by these therapies, contributing to an IFN-related DNA damage resistance signature (IRDS).
- The precise mechanisms linking DNA damage to IFN signaling and resistance remain unclear.
Purpose of the Study:
- To elucidate the mechanisms by which cancer therapies induce type I IFN signaling.
- To identify the cellular components involved in generating DNA fragments that activate IFN signaling.
- To explore the prognostic significance of these components and their therapeutic potential.
Main Methods:
- Investigated the release of single-stranded DNA (ssDNA) fragments into the cytosol following DNA-damaging cancer therapies.
- Assessed the roles of DNA end resection factors, specifically Bloom syndrome (BLM) helicase and Exonuclease 1 (EXO1), in generating these fragments.
- Examined the function of the exonuclease Trex1 in degrading these cytoplasmic DNA fragments.
- Analyzed mRNA expression profiles in breast tumors to correlate gene expression with patient prognosis.
Main Results:
- DNA-damaging cancer therapies induce the release of nuclear ssDNA fragments into the cytosol.
- BLM helicase and EXO1 are critical for generating these ssDNA fragments.
- Trex1 is essential for the degradation of these cytoplasmic ssDNA fragments.
- Lower Trex1 and higher BLM/EXO1 expression in breast tumors correlate with poor prognosis.
Conclusions:
- Cancer therapy-induced DNA damage triggers innate immune signaling via cytoplasmic ssDNA.
- BLM and EXO1 are key mediators in generating the DNA damage response signature (IRDS).
- Targeting BLM and EXO1 may offer a novel strategy to overcome therapeutic resistance mediated by IRDS.
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