RNA editing framework for disease-causing parasite identified - Newswise

Newswise — For years, Ruslan Afasizhev and Inna Afasizheva, a husband-and-wife team of molecular biologists at Boston University, have collaborated closely. Their joint efforts have resulted in numerous publications exploring the intricacies of mitochondrial DNA and RNA mechanics in a single-celled, pathogenic parasite known as Trypanosoma brucei. After countless breakthroughs in their research, their most recent achievement is a remarkable paper published in Science. This groundbreaking study delves into the enigmatic process of RNA editing, offering a comprehensive understanding that holds the potential to advance treatments for a fatal disease.

Afasizhev and Afasizheva, in conjunction with researchers from UCLA, University of California, Irvine (UCI), and ShanghaiTech University, have recently published a groundbreaking paper. Their study marks the first successful determination of the intricate architecture of molecular machines responsible for housing gRNA strands and facilitating their interaction with mRNA. This crucial discovery could provide scientists with vital insights for effectively treating African sleeping sickness, a devastating disease caused by Trypanosoma and transmitted through tsetse flies. The illness is typically fatal, and current treatments often raise safety concerns, underscoring the significance of molecular investigations in advancing drug development for this condition.

Afasizheva, an associate professor of molecular and cell biology at Boston University Henry M. Goldman School of Dental Medicine, expresses excitement about the prospects ahead: "With our precise understanding of how proteins interact with RNA, we can now embark on broader research initiatives." This newfound knowledge opens up promising avenues for further exploration and discovery in the field.

Afasizhev, who is not only a professor of biochemistry at the Boston University Chobanian & Avedisian School of Medicine but also the corresponding author of the paper, highlights an important potential breakthrough: "If we can discover a method to inhibit the editing process, we could effectively eliminate the parasite without causing harm to human cells." This discovery holds significant promise in the pursuit of developing safer and more targeted treatments for African sleeping sickness, offering hope for those afflicted by this deadly disease.

Over time, RNA research has experienced significant advancements, paralleled by remarkable progress in cell imaging technology. Presently, the husband-and-wife team utilizes cryo-electron microscopy and molecular techniques to gain comprehensive insights into RNA editing processes. In their latest study, they discovered that a crucial protein complex known as the editosome plays a pivotal role in facilitating changes directed by gRNA. These changes occur as a sequence of uridine insertions and deletions within RNA. Within Trypanosoma, RNA editing serves a vital purpose: repairing damaged genes. Due to the parasite's high prevalence of DNA mutations, the genetic code becomes unreadable. However, through RNA editing, the edited mRNA becomes functional, fulfilling its essential role in the cell's processes. This revelation sheds light on the intricacies of RNA editing and its significance in maintaining cellular function within Trypanosoma.

RNA editing plays a crucial role in the regulation of various cellular processes across organisms possessing cells with nuclei and mitochondria. However, according to Afasizhev, the mechanisms of RNA editing differ substantially among these organisms, indicating their evolution for specific purposes unique to each species. This divergence in RNA editing mechanisms renders Trypanosomes' RNA editing particularly appealing as a therapeutic target for combatting the parasite's disease-causing effects, as it poses no interference with human cells. Having now unveiled the distinct protein structures involved in RNA editing in Trypanosomes, the researchers are embarking on the next phase of their investigation, aimed at identifying the enzymes responsible for initiating these reactions within the cell.

"The next question is how these reactions happen, how these enzymes come to the substrate, and how they create the magnificent work to change the RNA sequence," Afasizheva says.

With a vision to foster a new generation of students who can embrace and harness the technological advancements in their field, she and Afasizhev are eager to expand their lab's team. They aim to inspire and empower these budding researchers to take on the challenge of unraveling the intricacies of this complex puzzle, building on the progress they have achieved thus far. Together, they envision a collaborative effort that will propel the understanding of RNA editing and its implications to new heights.

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