Tumor Cell Mutations Might Be Linked to DNA-RNA Hybrids, Lead to Emergence of Carcinogenic Processes

Cancer is a multifactorial disease triggered by the dysfunction of several cellular processes that fuel uncontrolled cell proliferation. One of the features of cancer cells is genome instability, which is considered one of the main causes of cell transformation and cancer evolution.

Cancer-Associated Mutagenesis

Researchers from the University of Seville, CABIMER, and IRB Barcelona investigate the relationship between DNA-RNA hybrids and tumor cell mutations. They attempted to understand if such a connection has to do with the emergence of carcinogenic processes. Led by researchers Andrés Aguilera and Aleix Bayona Feliu, the team studied these factors to understand and assess the possible cancer risks.

In the study entitled "The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts," the experts show that chromatin and the factors that regulate it prevent the formation of DNA-RNA hybrids, which are considered a source of genomic instability. As these hybrids block the replication process, it increases chromosomal cleavages and collisions between replication and transcription.

The experts performed analyses of the silencing of the various chromatin remodeling factors in tumor cell cultures. From this study, it was found that chromatin is the first barrier to protect the integrity of the genome.

The research also involves a comparison of the genome databases of tumor cells. The findings suggest that genome sites enriched in DNA-RNA hybrids match the areas with the highest frequency of mutations observed in tumor cells.

The study does not only offer a better insight into the cellular control of hybrids and their regulation by epigenetic factors. For the first time, it was also revealed that there is a direct connection between DNA-RNA hybrids and cancer-related mutations, an indication that they are a risk factor in the development of tumors.

Understanding DNA-RNA Hybrids

Six decades ago, the concept that complementary DNA and RNA strands could pair to form a double helix structure was not so trivial. Nowadays, it is well known that DNA-RNA hybrids are abundant in living organisms, such as humans, and are primary physiological intermediates in many biological processes.

DNA-RNA hybrids serve as primers for DNA replication, regulating gene expression, and serving as structural components of particular eukaryotic genomic elements. The hybridization of DNA and RNA is also a crucial step in cell-specific processes, such as immunoglobulin class-switch recombination.

DNA-RNA hybrids may be formed as obligatory intermediates of both DNA and RNA synthesis processes. However, the formation of this hybrid also has a dark side. Previous studies suggest that accumulating long and stable DNA-RNA hybrids could harm the cells and make the genomes susceptible to rearrangements and breakages. These hybrids could trigger inaccurate DNA double-strand break repair pathways if they are not removed accurately.

These hybrids are an essential source of genome instability, a hallmark of cancer and genetic diseases. Because of this, detecting these hybrids in cells becomes crucial in understanding an increasing number of molecular biology processes in genome dynamics and function. They also play an essential role in identifying new factors and mechanisms responsible for disease in biomedical research.

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