Ribosomal rna methylation constrols the cell cycle through protein synthesis

Zusammenfassung

Cytosine-5 methylation (m5C) is one of the most well-known post-transcriptional modifications in RNA. This mark is predominantly found in transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) and is mediated by DNMT2 and NSUN family members. Recently, m5C modification on tRNAs has been shown to regulate stem cell function and stress response, and its inhibition specifically eliminates cancer initiating cells. This suggest that RNA methylation may regulate essential cellular and physiological processes and that its deregulation may lead to critical pathological consequences such as cancer. In contrast to tRNAs, the functional significance of m5C in other RNAs in which this mark is also prevalent, such as rRNAs, has not been deeply studied in mammals yet. NSUN5 is a m5C methyltransferase that targets position C3782 of 28S rRNA, located at the interface between large and small ribosome subunits. Depletion of NSUN5 is known to alter global protein synthesis, translation fidelity and cell growth. However, how the loss of this methylation affects these key cellular processes is not well-understood yet. Herein we show that NSUN5 loss-of-function in mammalian cells leads to reduced proliferation rates, primarily due to an impaired progression through the G2/M phases of the cell cycle. Mechanistically, reduced m5C deposition at C3782 alters ribosomal structure and induces a translational shift, favoring the synthesis of ribosomal proteins and cell cycle regulators. Moreover, we have found that NSUN5 is post-translationally modified by CDK1 during mitosis, resulting in its destabilization. These findings suggest that NSUN5 expression is temporary modulated during the cell cycle to fine-tune translation and ensure proper progression through this critical cellular process. Furthermore, our investigation reveals that NSUN5 is overexpressed in several cancers, particularly during advanced stages, correlating with increased risk of recurrence. While Nsun5 deficiency does not affect primary tumor growth in vivo, it significantly impairs tumor metastatic potential, indicating that NSUN5 may serve as therapeutic target to combat tumor metastasis.