Study Reveals a Form of Four-Stranded DNA that Links Protein Deficiency and Premature Aging

A recent study by researchers at the Molecular Science Research Hub at Imperial College London has shown that the Cockayne Syndrome B (CSB) protein can selectively bind with intermolecular G-quadruplexes (G4s) of ribosomal DNA (rDNA). The authors claimed that this is the first study showing an endogenous protein with a higher affinity and specificity binding with intermolecular G4s over intramolecular ones, which are the primary focus of previous studies. Besides, the loss of function of CSB affects the cellular homeostasis and evokes a premature aging phenotype due to the unresolved G4s structures.

The paper, titled “Cockayne Syndrome B Protein Selectively Resolves and Interact with Intermolecular DNA G-Quadruplex Structures.”, was published in the Journal of the American Chemical Society.

What are Guanine-Quadruplexes (G4s)?

G4s, the secondary DNA or RNA structures, result from the folding of guanine-rich motif. Human rDNA is guanine-rich, and rDNA transcription may promote G4s formation; however, the loss of rDNA transcription can lead to mitochondrial dysfunction, which is one cause of aging or cellular senescence. In addition, lacking CSB results in mitochondrial dysfunction and transcriptional halt at rDNA G4s in human cells, suggesting the function of CSB to resolve rDNA G4s and maintain rDNA transcription and mitochondrial function.

Cockayne Syndrome and Aging

Cockayne syndrome (CS) is a rare autosomal recessive disorder (1 in 250,000 incidence) and was first described in 1936. Most CS cases (70-75%) results from the mutation on the gene of CSB. CS shares many clinical features of normal human aging, including but not limited to hearing loss, cataracts, retinal dystrophy, neurological manifestations, or other organs/systems pathologies (e.g., cardiovascular system dysfunction and endocrine dysregulation). Interestingly, antioxidant supplements (e.g. NAD+) can reverse CS-associated hearing loss, restore mitochondrial homeostasis, and promote DNA repair. Further investigation of the molecular mechanisms of CS may provide more insights into the progression of aging.

Aging has become a universal biological phenomenon and issue, and the population over 60 years old is expected to increase from 12% to 22% between 2015 and 2050, according to the WHO. Genomic instability, mitochondrial dysfunction, and cellular senescence are three of the major hallmarks of aging. G4s accumulation on rDNA can cause mitochondrial dysfunction, meaning one of the CSB functions, resolving G4s in rDNA, is critical to prevent aging. Moreover, the failure of resolving G4s at telomeres can induce telomere dysfunction and promote immortality in cancerous cells during mitosis, suggesting G4s as a target for gerontology or oncology research.

In brief, since CS encapsulates the characteristics of aging, developing the therapeutics to restore CSB function, treat CS, or resolve G4s is a potential way to increase genomic stability and prevent aging.

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