Role of cytosine-5 methylation of ribosomal RNA in cell cycle control
Judith López Luis
Centro de Investigación del Cáncer (CIC-IBMCC)
5-methylcytosine (m5C) is the most well-known modification in DNA, but it is also very common in RNA. However, while the functions of m5C in DNA have been extensively studied, its role in RNA is emerging to be elucidated. m5C deposition is found mainly in transfer RNA (tRNA) and ribosomal RNA (rRNA) and is mediated by DNMT2 and NSUN family members. Recently it has been shown that m5C on tRNAs regulates stem cell functions and stress responses in normal epidermis and skin cancer, and its inhibition specifically eliminates cancer initiating cells, suggesting that RNA methylation may regulate essential cellular and physiological processes and its dysregulation may lead to critical pathological consequences such as cancer.
In contrast to tRNAs, the functional role of m5C in other RNAs in which this mark is prevalent like rRNA has not been deeply studied in mammals yet. NSUN5 is a m5C methyltransferase that methylates position C3872 of 28S rRNA, located at the interphase between small and large ribosome subunits and its depletion alters global protein synthesis and translation fidelity. In vitro analysis using NSUN5-silenced cell lines showed that its depletion leads to impaired proliferation and cell cycle progression, indicating a role of NSUN5-mediated methylation in the regulation of these key processes. In addition, our data shows that NSUN5 expression is crucial to maintain the translational program of the cell in order to guarantee the cell cycle progression.
Cell cycle dysregulation is a key event that governs aberrant proliferation of cancer cells. Thus, cell cycle has been a target for drug development for many years, with promising preclinical and clinical data. NSUN5 is overexpressed in several cancers such as advanced metastatic PCa, glioma, diffuse large B-cell lymphoma and liver hepatocellular carcinoma, among others, indicating that it could be a potential molecular target for cancer treatment.