Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.

Area of Science:

• Genetics and Genomics
• Cancer Biology
• Metabolic Disease Research

Background:

• Obesity is a known risk factor for various cancers, but the precise molecular mechanisms are not fully understood.
• Genomic instability, often driven by disruptions in metabolic and cellular pathways, is a hallmark of obesity-associated cancers.
• Repetitive DNA sequences forming alternative structures like H-DNA are implicated in mutation hotspots within cancer genomes.

Purpose of the Study:

• To investigate whether obesity influences endogenous mutation hotspots mediated by DNA repeats.
• To determine the impact of obesity on DNA damage and mutation frequencies at H-DNA-forming sequences.
• To assess DNA repair efficiency in obese versus normal-weight models.

Main Methods:

• Utilized transgenic reporter mice with either B-DNA or H-DNA forming sequences (derived from the c-MYC translocation hotspot).
• Compared mutation frequencies and DNA damage levels between obese and normal-weight mice.
• Evaluated tissue-specific DNA repair efficiency in both groups.

Main Results:

• Obesity significantly elevated H-DNA-induced DNA damage and mutation frequencies in a tissue-specific manner.
• DNA repair efficiency was demonstrably reduced in obese mice compared to control mice.
• These findings highlight a direct link between obesity and increased endogenous mutations at specific genomic sites.

Conclusions:

• Obesity exacerbates DNA damage and mutations at H-DNA-forming hotspots, contributing to genomic instability.
• Reduced DNA repair capacity in obesity plays a mechanistic role in cancer development.
• This research provides crucial insights into how obesity promotes cancer through endogenous mutagenic processes.