NAT10 in RNA Acetylation, Gene Expression, and DNA Repair

NAT10 is an enzyme involved in RNA modifications, gene regulation, and DNA repair. Its activity influences cellular processes such as protein synthesis and genome stability, making it a key player in maintaining normal cell function. Given its broad impact, NAT10 has drawn attention for its potential roles in disease development and therapeutic targeting.

Biochemical Function In RNA Acetylation

NAT10 functions as an RNA acetyltransferase, catalyzing the transfer of an acetyl group to cytidine residues in RNA. This enzymatic activity results in the formation of N4-acetylcytidine (ac4C), a modification identified in both messenger RNA (mRNA) and ribosomal RNA (rRNA). Acetylation influences RNA stability, translation efficiency, and function, making NAT10 a key regulator of post-transcriptional gene expression. The presence of ac4C has been linked to enhanced codon recognition and improved translation fidelity, suggesting a role in optimizing protein synthesis.

The catalytic mechanism of NAT10 involves its GNAT (GCN5-related N-acetyltransferase) domain, which transfers an acetyl group from acetyl-CoA to cytidine. Structural studies show NAT10’s substrate specificity, targeting cytidine residues in certain sequence contexts influenced by RNA secondary structures and interactions with other RNA-binding proteins. NAT10’s localization in the nucleolus supports its role in modifying rRNA, contributing to ribosome biogenesis and translational accuracy. Disruptions in NAT10 activity are associated with ribosomal dysfunction, leading to protein homeostasis defects.

Beyond rRNA, NAT10-mediated acetylation in mRNA affects transcript stability and translation dynamics. High-throughput sequencing, such as acRIP-seq, has mapped ac4C modifications across the transcriptome, showing enrichment in coding sequences and untranslated regions. These modifications enhance mRNA stability by reducing exonuclease susceptibility, prolonging transcript half-life. Ac4C also promotes ribosome engagement and elongation, fine-tuning gene expression at the post-transcriptional level.

Role In N4-Acetylcytidine Formation

NAT10 is the primary enzyme catalyzing cytidine acetylation at the N4 position, producing ac4C, a modification detected in multiple RNA species. This process relies on acetyl-CoA as an acetyl donor, facilitated by NAT10’s GNAT domain. Structural analyses reveal that NAT10 recognizes specific cytidine residues based on sequence context and RNA secondary structure, ensuring precise ac4C formation. This modification has been confirmed in rRNA, where it optimizes ribosome function, and in mRNA, where it influences translation.

Ac4C incorporation enhances RNA stability and translational efficiency, particularly in mRNAs encoding highly expressed proteins. AcRIP-seq studies show ac4C enrichment in coding and untranslated regions, indicating targeted regulation of gene expression. Ac4C-modified transcripts exhibit increased resistance to exonucleolytic degradation, prolonging mRNA half-life. Additionally, ac4C improves codon-anticodon interactions, reducing ribosomal stalling and enhancing translation fidelity.

Ribosomal RNA modifications, including ac4C, contribute to ribosome integrity and accurate mRNA decoding. NAT10 localizes to the nucleolus, where rRNA processing occurs, supporting its role in ribosome assembly. Disruptions in ac4C formation impair translation and cellular function. NAT10 depletion reduces ac4C levels in rRNA, correlating with compromised ribosomal activity and decreased global protein synthesis, highlighting its role in translational homeostasis.

Gene Expression Modulation

NAT10 influences gene expression by modifying RNA structure and function, shaping protein synthesis efficiency and accuracy. RNA acetylation alters transcript stability, translation dynamics, and ribosome interactions, leading to selective regulatory effects. NAT10 does not act uniformly across all transcripts but exerts targeted control over specific genes.

NAT10’s presence in the nucleolus and cytoplasm suggests it operates at multiple regulatory levels. In the nucleolus, it influences the maturation of RNA species essential for translation, while in the cytoplasm, its modifications affect mRNA stability and ribosomal engagement. Certain transcripts display increased translation efficiency following NAT10-mediated acetylation, particularly those involved in metabolism and cell cycle progression. This targeted enhancement allows cells to adjust protein production in response to physiological demands.

NAT10 also plays a role in stress responses and proliferation. Cells experiencing environmental stress exhibit altered NAT10 activity, leading to shifts in gene expression that support adaptation and survival. NAT10 inhibition results in widespread transcript stability changes, with some mRNAs showing reduced half-lives while others become more stable. This suggests NAT10 operates within a complex regulatory network that fine-tunes gene expression in response to cellular needs.

Tissue Variations In NAT10 Activity

NAT10 expression and activity vary across tissues, reflecting distinct regulatory needs. Highly proliferative tissues like bone marrow and intestinal epithelium display elevated NAT10 levels, aligning with their demand for robust RNA processing and protein synthesis. In contrast, quiescent tissues like skeletal muscle show lower NAT10 activity, suggesting its role is more pronounced in rapidly dividing cells.

Neuronal tissues require a precise balance of NAT10 activity to support synaptic function and neuroplasticity. NAT10 expression is enriched in brain regions associated with learning and memory, indicating a role in synaptic protein synthesis. Disruptions in NAT10 activity have been linked to neurodegenerative conditions, further emphasizing its importance in neuronal homeostasis.

DNA Damage Response

NAT10 plays a crucial role in maintaining genomic integrity, particularly in response to DNA damage. Cells are constantly exposed to stressors that cause DNA lesions, including oxidative stress, ultraviolet radiation, and chemical mutagens. NAT10 has been implicated in DNA repair pathways, particularly in responding to double-strand breaks (DSBs) and other genotoxic insults.

One mechanism by which NAT10 facilitates DNA repair is through interactions with chromatin-associated proteins. RNA acetylation has been linked to chromatin remodeling, influencing the accessibility of repair enzymes to damaged DNA sites. NAT10 modulates the acetylation of non-coding RNA species that interact with chromatin, affecting DNA repair complex dynamics. Depleting NAT10 leads to delayed repair kinetics and increased sensitivity to genotoxic agents, indicating its role as a regulatory checkpoint ensuring an efficient genomic stress response.