🧬 PubMed RNA Editing Daily Digest

Prime editing has recently gained attention for its promising potential in treating genetic disorders caused by different types of mutations. This method, based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), has led to the development of new strategies that offer improved editing efficiency. Additionally, the components of prime editing-namely, the prime editor (PE) and the prime editing guide RNA (PegRNA)-have been enhanced through rational design and direct evolution of structural modifications. These improvements have resulted in better performance and new capabilities, driven by novel mutations or components. In this review, we compare various studies that report enhanced versions of PE or PegRNA, which achieve more efficient results. These advancements hold the potential to accelerate and simplify the development of gene therapies for a range of genetic disorders.

Clustered Regularly Interspaced Short Palindromic Repeat-associated proteins (CRISPR-Cas) biochemistry has been leveraged in genome editing applications in biochemical research and therapeutics. CRISPR-Cas9 and CRISPR-Cas12a are the two most widely used RNA-guided endonucleases and while Cas9 and Cas12a have a shared function, both have unique biophysical properties that alter their specificity and efficiency. The thermodynamic and kinetic properties governing their molecular interactions, recognition and binding of target DNA, and R-loop formation can differ. In some cases, these critical biophysical metrics have not been resolved. Distinctions between Cas9 and Cas12a enzymes are also prevalent in RNA:DNA hybrid binding affinities, DNA localization relative to the preferred PAM site and DNA cleavage mechanism. In this review, we examine the biophysical properties of both endonucleases, focused on the nucleic acid interactions that confer specificity and function. Complementing this biophysical overview, we discuss case studies in disparate model organisms that compare the genome editing and fidelity of Cas9 and Cas12a.

Functional adenosine-to-inosine mRNA editing sites are continuously identified in cellular organisms. Despite that several editing sites have been linked to various human cancers, the dynamic RNA editing in the progression of myeloid neoplasms remains less known, preventing a clearer understanding of the functional repertoire of RNA editing in blood diseases. By analyzing transcriptomes from healthy controls, low-risk myelodysplastic syndrome, high-risk myelodysplastic syndrome, and acute myeloid leukemia, we reveal widespread and dynamic RNA editing events accompanying disease progression. Immunoglobulin genes are enriched for nonsynonymous editing sites with significantly altered editing levels in myeloid neoplasms, and such recoding sites often show genomic substitutions to hardwired G during mammalian evolution. Collectively, our findings broaden the functional spectrum of RNA editing in human and highlight its potential as a driver, responsor, or biomarker of myeloid neoplasms, underscoring its significance in human disease evolution.

Colorectal cancer (CRC) is traditionally considered a "cold tumor" characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair-proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair-deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations-including RNA editing-act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy.