TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells

Area of Science:

• Genetics
• Molecular Biology
• Aging Research

Background:

• The human TP53 gene exhibits a common polymorphism at codon 72, resulting in Arginine (p53R72) or Proline (p53P72) isoforms.
• These p53 isoforms differ in subcellular localization and function, particularly in DNA repair pathways.
• p53 plays a role in maintaining mitochondrial DNA (mtDNA) integrity, but the isoform-specific effects on mtDNA damage are unclear.

Purpose of the Study:

• To investigate whether the TP53 codon 72 polymorphism influences the accumulation of mtDNA damage.
• To explore the association between p53 isoforms, polymerase gamma binding, and mtDNA damage in vitro and in vivo.

Main Methods:

• Comparison of mtDNA damage accumulation in cells expressing p53R72 versus p53P72 isoforms under rotenone stress.
• Assessment of p53 isoform co-localization with polymerase gamma.
• Analysis of mtDNA heteroplasmy levels in the D-loop region of 425 aged subjects.

Main Results:

• Cells with the p53R72 isoform accumulated less mtDNA damage compared to p53P72 cells after rotenone exposure.
• The p53R72 isoform showed greater co-localization with polymerase gamma than the p53P72 isoform.
• Individuals with the p53R72/R72 genotype had significantly lower-than-expected levels of mtDNA heteroplasmy (>5%).

Conclusions:

• The TP53 codon 72 polymorphism influences mtDNA damage accumulation.
• The p53R72 isoform may offer better protection against mtDNA damage, potentially via enhanced binding to polymerase gamma.
• This polymorphism could contribute to variations in mtDNA mutation accumulation during aging.