Each living cell must interpret its genetic code – a sequence of chemical letters governing countless cellular functions. A new study by researchers from the Theoretical Organic Physics Center at Rice University has revealed the mechanism by which the identity of the letters following a given nucleotide in DNA affects the possibility of errors during the transcription, the process by which DNA is copied to RNA. The discovery offers a new image for hidden factors that affect the accuracy of the transcription.
The study, compiled by Tripti Midha, Anatoly Kolomeisky and Oleg Igoshin and published in The Proceedings of the National Academy of Sciences On July 9, it shows why genetic sequences are not just as prone to errors. Instead, the identity of the two nucleotides immediately downstream of a position significantly changes the error rate during the transcription. This discovery is based on previous ideas by the same authors on enzymatic correction mechanisms, producing the effects of separate kinetics for different nucleotide additions.
It is not only the letter itself that matters, but the neighbor’s neighbors. ”
Oleg Igoshin, Professor of Biomedical, Chemistry and Bioe Sciences
Kinetic speed and sequence dependence
The cells are based on RNA polymerases to transcribe DNA to high fidelity RNA. Although error rates are generally low, occasional errors can disrupt protein function or regulation. Until now, the mechanisms of how the local DNA framework affects these errors were not well understood.
The research team developed a theoretical framework that links the faithfulness of the transcription to the speed of nucleotide integration. Their model suggests that faster built -in bases, such as adenine (A) and Guanin (G), reduce the time available to correct errors (correction), thereby increasing error rates. In contrast, slower built -in bases, such as cytosine (C) and uracil (U), allow more time to correct errors.
The researchers examined their model in a series of recently published experimental databases and found a strong agreement in various genomic frames.
“The kinetic authorities we have developed can predict areas where errors are likely to occur, extending to previous transcript loyalty models that do not disclose a long -range dependence,” Igoshin said.
Impact on the risk of genetic disease
To understand the consequences, the study focused on the BRCA1 gene, which plays a critical role in preventing breast and ovarian cancer. With the analysis of BRCA1’s nucleotide sequence, the group discovered that errors dependence affects the likelihood of premature attitude codes. An premature attitude codon can cut the BRCA1 protein, reducing its function in DNA repair and lifting the risk of cancer.
The increased rates of premature termination caused by dependent transcription errors in important genes such as BRCA1 reveal a previously unrecognized layer of genetic vulnerability, deepening the understanding of the mechanisms of the disease and hereditary risk, said Kolomeis.
“Researchers now have a tool to make them better map and predict where harmful transcription errors may occur,” Kolomeisky said.
To prognostic and preventive strategies
By clarifying the way in which DNA sequence affects the accuracy of the transcription, the study offers a new perspective for its loyalty, suggesting that errors are not in random positions but are affected by the nucleotide motor rhythms
“Biotechnologists could use this model to design gene sequences with inherently lower rates of error, possibly improve fractions without synthetic and therapeutic RNA errors,” said Midha, a postdoctoral collaborator at the Theoretical Center.
This research was supported by the National Foundation of Sciences and the Welch Foundation.
Source:
Magazine report:
Midha, T., et al. (2025). Motor mechanisms to depend on the sequence of transcriptional errors. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2505040122.
