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Updated: Nov 10, 2025
Author Spotlight: Decoding DNA Repair by Extrachromosomal NHEJ Assay and HR Assays
Published on: February 2, 2024
Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer's Achilles' Heel
Daniele Caracciolo1, Caterina Riillo1, Maria Teresa Di Martino1
1Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, 88100 Catanzaro, Italy.
Abstract:
Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer's Achilles' heel to be therapeutically exploited in precision oncology.
Insights
The alternative non-homologous end joining (Alt-NHEJ) pathway drives cancer genomic instability. Targeting Alt-NHEJ offers a new strategy for precision oncology treatments, potentially enhancing immunotherapy effectiveness.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Genomic instability, driven by error-prone DNA repair, fuels cancer development.
- The alternative non-homologous end joining (Alt-NHEJ) pathway is implicated in cancer progression and drug resistance.
- Understanding Alt-NHEJ mechanisms is crucial for developing novel cancer therapies.
Purpose of the Study:
- To review recent findings on the role of Alt-NHEJ in promoting genomic instability.
- To highlight Alt-NHEJ as a potential therapeutic target in precision oncology.
- To explore the exploitation of Alt-NHEJ in synthetic lethality and immunotherapy.
Main Methods:
- Literature review of experimental evidence on Alt-NHEJ components (LIG3, PolQ, PARP1).
- Analysis of the association between Alt-NHEJ up-regulation and cancer hallmarks.
- Discussion of therapeutic strategies targeting DNA damage response (DDR) pathways.
Main Results:
- Up-regulation of key Alt-NHEJ factors (LIG3, PolQ, PARP1) is observed in various tumors.
- Alt-NHEJ activity is linked to cancer progression, drug resistance, and increased mutational load.
- Cancer cells exhibit addiction to Alt-NHEJ, presenting a vulnerability.
Conclusions:
- Alt-NHEJ is a significant driver of genomic instability and a critical factor in cancer.
- Targeting Alt-NHEJ offers a promising avenue for synthetic lethality approaches in cancer treatment.
- Exploiting Alt-NHEJ can enhance the efficacy of immunotherapy by increasing tumor mutational burden.
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