SMN-deficient cells exhibit increased ribosomal DNA damage

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from reduced survival motor neuron (SMN) protein levels.
• SMN protein is crucial for various cellular functions, with emerging evidence highlighting its role in DNA integrity maintenance.
• Ribosomal DNA (rDNA) is a known unstable genomic region prone to breakage, and its instability is implicated in aging and neurodegenerative diseases.

Purpose of the Study:

• To investigate the role of SMN protein in maintaining DNA integrity, specifically at the rDNA locus.
• To explore the consequences of SMN deficiency on rDNA stability and associated cellular processes.
• To identify potential molecular mechanisms linking SMN deficiency to rDNA instability in the context of SMA.

Main Methods:

• Utilized cell models deficient in SMN protein.
• Assessed rDNA damage and genomic instability.
• Measured ribosomal RNA (rRNA) synthesis and protein translation rates.
• Investigated interactions between SMN and RNA polymerase I.
• Examined the expression and localization of DDX21 protein in SMA motor neurons.

Main Results:

• SMN-deficient cells displayed significant increases in rDNA damage.
• Impaired rRNA synthesis and translation were observed in SMN-deficient cells.
• An interaction between SMN and RNA polymerase I was identified.
• A deficiency of DDX21, a protein involved in resolving R-loops, was found specifically in SMA motor neurons.

Conclusions:

• SMN protein plays a critical role in maintaining rDNA integrity.
• SMN deficiency leads to rDNA instability, affecting fundamental cellular processes like RNA synthesis and translation.
• The findings reveal a novel mechanism involving SMN, RNA polymerase I, and DDX21 in rDNA stability, offering new insights into SMA pathogenesis.