The latest research in the field of DNA repair brings revolutionary insights that could enhance cancer treatment, particularly in cases of colorectal cancer, the second leading cause of cancer-related mortality worldwide. Scientists from prestigious institutions such as the University of Oxford and Nanyang Technological University in Singapore have discovered a key mechanism in repairing damaged DNA, a process known as nucleophagy, which holds significant potential for improving chemotherapy outcomes in cancer patients.

DNA damage can be caused by numerous factors, including UV radiation, environmental chemicals, and natural biological processes. Classical DNA repair mechanisms are focused on repairing within the nucleus and mitochondria, where the genetic material resides. However, the latest discovery shows that damaged DNA can be removed from the nucleus via nucleophagy. This process allows for the elimination of damaged DNA fragments through cellular waste systems, preserving genome integrity and extending cell life.

A new repair pathway: nucleophagy and the role of the TEX264 protein

The key player in this process is the TEX264 protein, which recognizes DNA damage and directs it to cellular organelles responsible for degradation—lysosomes. TEX264 facilitates the removal of damaged DNA fragments, which is crucial for cell survival under chemotherapy stress. This mechanism ensures that DNA damage is removed before it causes mutations that could lead to tumor formation.

Studies have shown that patients with elevated levels of TEX264 protein have better responses to therapy, particularly to colorectal cancer treatment with chemotherapy involving topoisomerase I inhibitors, such as FOLFIRI therapy. These insights allow for predicting the effectiveness of therapy based on the levels of this protein in tumor cells, opening the door to more precise therapeutic approaches. Scientists believe that targeting this protein could weaken tumor cells and improve treatment outcomes.

Zebrafish: a key model for studying cellular processes

In studies using zebrafish, organisms whose genome is remarkably similar to humans, scientists have been able to show how the inactivation of the TEX264 protein leads to the accumulation of DNA damage. This model allows for the tracking of cellular processes in real-time, and thanks to transparent embryos and external fertilization, researchers can easily observe how cells respond to DNA damage. Zebrafish provide a simple and effective model for investigating DNA damage mechanisms and their impact on disease development.

These zebrafish have been used in conjunction with advanced techniques such as biochemical analysis, mass spectrometry, and bioinformatics to precisely determine how TEX264 participates in DNA repair. Researchers have also utilized tissue samples from patients with colorectal cancer to validate findings from zebrafish, demonstrating that this process is crucial for maintaining genome stability in the context of therapies.

Key implications for future treatment

One of the most important discoveries is the potential for blocking TEX264 as a strategy to enhance chemotherapy. Combining inhibitors of this protein with existing drugs could further weaken tumor cells and prevent them from repairing DNA damage, thereby increasing therapy effectiveness. This discovery not only opens doors to new approaches for treating colorectal cancer but could also extend to other types of tumors, including pancreatic, ovarian, breast, and lung cancers.

The research results represent a crucial step forward in understanding how cells maintain DNA integrity under therapy stress and offer hope for patients whose cancer shows resistance to standard treatments. Future studies will focus on further exploring the role of nucleophagy in response to chemotherapy drugs, aiming to confirm these findings in the context of other types of cancer.

Laboratory research and advanced technologies

At the Ruđer Bošković Institute, researchers have established a top-tier laboratory for studying zebrafish, utilizing advanced technologies such as the CRISPR-Cas system for genetic manipulation. This allows for the creation of new strains of zebrafish that are crucial for investigating human diseases. Zebrafish are also in compliance with EU commission guidelines for the use of animal models in scientific research, thereby reducing the reliance on more complex models like rodents. This model offers invaluable assistance in biomedical research, particularly for diseases such as cancer, neurodegenerative diseases, and heart problems.

The potential for utilizing zebrafish in laboratories worldwide further emphasizes their value in modern medicine. Scientists around the globe are increasingly recognizing the importance of this model organism, indicating a broader application of research techniques that have already been developed in laboratories such as the Ruđer Bošković Institute.

Source: Ruđer Bošković Institute