The
Ataxia-telangiectasia mutated protein kinase (ATM) is traditionally known for
its role in DNA damage response, particularly in sensing and repairing DNA
double-strand breaks. However, recent research has uncovered novel cytoplasmic
functions of ATM in neurons that extend beyond its canonical role in DNA
repair. Here are some key points regarding the cytoplasmic function of ATM in
neurons:
1. Regulation of
Nucleolar Transcription:
o ATM Activation: In neurons, ATM
has been identified as a regulator of RNA-Polymerase-1 (Pol-1)-mediated
transcription of nucleolar rRNA genes (rDNA). Activation of ATM, even at low
concentrations of DNA double-strand break inducers, stimulates rDNA
transcription in cortical neurons.
o Transcriptional
Regulation: ATM
positively regulates nucleolar transcription by modulating the activity of
Pol-1, which is essential for ribosomal RNA synthesis and ribosome biogenesis.
Dysregulation of nucleolar transcription due to ATM deficiency may contribute
to neurodegenerative processes.
2. Nucleolar
Localization:
o ATM Localization: Interestingly,
ATM has been found to be robustly present in neuronal nucleoli, the subnuclear
compartments responsible for ribosome biogenesis. This localization suggests a
direct role for ATM in regulating nucleolar functions and ribosomal biogenesis in
neurons.
o Phosphorylation
Targets: Critical
regulators of Pol-1, the enzyme responsible for rRNA synthesis, display
potential ATM phosphorylation sites. This indicates that ATM may directly
modulate the activity of nucleolar transcription factors to regulate ribosomal biogenesis.
3. Neurodegenerative
Implications:
o Defective
Ribosomal Biogenesis: Dysregulation of nucleolar transcription and ribosome biogenesis, as
observed in ATM-deficient neurons, may contribute to neurodegenerative
processes. Impaired ribosomal biogenesis can lead to disruptions in protein
synthesis, cellular homeostasis, and neuronal function, potentially
exacerbating neurodegenerative conditions.
o ATM-Related
Disorders: Mutations
in the ATM gene are associated with Ataxia-telangiectasia (A-T), a
neurodegenerative disorder characterized by progressive cerebellar degeneration
and increased cancer susceptibility. The cytoplasmic functions of ATM in
nucleolar transcription provide insights into the pathophysiology of A-T and
related neurodegenerative conditions.
4. Therapeutic
Implications:
o Targeting
Nucleolar Transcription: Modulating nucleolar transcription and ribosome biogenesis pathways
regulated by ATM could offer novel therapeutic strategies for neurodegenerative
disorders associated with ATM dysfunction. Targeting ribosomal biogenesis
processes may help restore neuronal homeostasis and function in these conditions.
o Precision
Medicine Approaches: Understanding the cytoplasmic functions of ATM in neurons opens up
avenues for precision medicine approaches that target nucleolar transcription
pathways specifically in neurodegenerative disorders linked to ATM
abnormalities. Tailored interventions aimed at restoring nucleolar function
could hold promise for disease management.
In conclusion,
the cytoplasmic function of ATM in neurons, particularly its role in regulating
nucleolar transcription and ribosomal biogenesis, represents a novel aspect of
ATM biology beyond its canonical DNA damage response functions. Dysregulation
of ATM-mediated nucleolar processes may contribute to neurodegenerative
conditions, highlighting the therapeutic potential of targeting these pathways
in neuronal disorders.
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