Targeting NMD has the potential to open new avenues for precision cancer therapy by revealing the previously unrealized immunogenic potential of tumors and bridging the gap between RNA biology and cancer immunotherapy.
The CRISPR strategy shows compelling evidence as a therapeutic approach targeting PE in cancer and other human diseases as well as the preferential advantages of CRISPR over the antisense technology recently developed targeting the PE of EZH2.
Overall, the findings suggest that TA is not a universal response to loss-of-function mutations in yeast, and the ability to resist specific transcriptomic ruptures would thus rely mostly on the general robustness of genetic networks.
Marzena Marszałek, W. Babik, R. Korona et al.· Molecular biology and evolut...· 0 citations
Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC – as a TMBhigh cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.
Lucia A. Torres-Fernández, V. Boehm, Joel Kaufmann et al.· Molecular Cancer· 0 citations
Nonsense-mediated decay (NMD) is a vital RNA surveillance mechanism in eukaryotic cells that ensures mRNA quality and regulates gene expression. NMD targets mRNAs with premature translation-termination codons to prevent the production of potentially harmful truncated proteins. But NMD is also involved in modulating the expression of physiological mRNAs to maintain cellular homeostasis. This NMD function is particularly relevant to calibrate the cellular transcriptome in response to environmental signals and stress. Its conservation across eukaryotes highlights its essential role. When active, NMD promotes mRNA degradation involving exoribonucleases like XRN1 (5' to 3') and the exosome (3' to 5'). DIS3L2, an exosome-independent exonuclease that primarily targets substrates marked by the non-templated addition of uridine residues to the 3' end of RNA molecules by terminal uridylyl transferases, can also degrade some NMD substrates, especially those that underwent 3' end uridylation. This review explores DIS3L2's interaction with the NMD pathway (DIS3L2/NMD pathway) and the human disorders associated with a dysfunctional DIS3L2/NMD pathway. A better understanding of the interplay between NMD and DIS3L2 will certainly allow the development of novel treatments for disorders associated with an affected DIS3L2/NMD pathway.
Rafaela Lacerda, Miguel Carvalho, L. Romão· Journal of Molecular Biology· 1 citation
Aberrant pre-mRNA splicing in cancer generates protein sequences that are rare or absent in normal tissues, creating a rich source of tumor-specific neoantigens for immunotherapy. These splicing-derived neoantigens arise through diverse mechanisms, including recurrent somatic mutations in core spliceosome components (SF3B1, SRSF2, U2AF1, and ZRSR2), epigenetic derepression of transposable elements that give rise to chimeric exon-TE junctions, and coordinated dysregulation of splicing regulatory networks in cancers lacking spliceosome coding mutations. These processes produce two major classes of immunotherapeutic targets: 1) MHC class I-restricted neopeptides that can be recognized by T-cell-based therapies, and 2) extracellular neoepitopes (ExNeoEpitopes) within transmembrane proteins that are accessible to HLA-independent antibody-based modalities, including monoclonal antibodies (mAbs), bispecific engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T or CAR-NK cells. Despite their strong immunogenic potential, effective therapeutic exploitation requires overcoming key immunological barriers, including T-cell exhaustion, impaired antigen presentation through MHC-I downregulation, and suppression within the tumor microenvironment. Recent advances in computational neoantigen prediction, immunopeptidomics, surface proteomics, long-read and single-cell isoform sequencing, and AI-guided therapeutic design are enabling more systematic discovery and validation of splicing-derived targets. This review integrates current understanding of the biological origins, immunological barriers, target classes of splicing neoantigens, and the technologies that enable their advancement in cancer immunotherapy.
Mu-Tian Tang, H. L. Grimes, Nathan Salomonis· Frontiers in Immunology· 0 citations
Transcription blockage frequently occurs in tumor cells, and aberrant R-loop formation during this process drives genome instability. However, the regulation of R-loop homeostasis and its contribution to tumorigenesis remain to be investigated. Here, we report that the RNA exonuclease REXO4 resolves R-loops by 3'-5' exonucleolytic cleavage of the RNA strand within RNA-DNA hybrids. Accessible RNA ends, generated by endonucleases, are required for this process, and N6-methyladenosine (m6A) modification on RNA moieties promotes REXO4 localization and R-loop removal in human cells. REXO4 ablation-induced DNA damage stimulates an interferon response and tumor immune infiltration, suppressing mouse squamous cell carcinoma (SCC) progression. Importantly, inhibition of REXO4 potentiates the anti-tumor efficacy of PD-1 blockade against SCC by recruiting and activating CD8+ T cells. Thus, our study provides mechanistic insight into how m6A couples with an exonuclease in R-loop clearance and genome maintenance and uncovers a druggable epitranscriptional machinery that constrains the innate immune response and enables SCC immune evasion.
Jieyou Zhang, Kaiwen Bao, Yayan Hou et al.· Molecules and Cells· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
