miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and...

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• MicroRNA-155 (miR-155) is an oncogenic microRNA frequently overexpressed in various cancers, correlating with poor patient prognosis.
• Its overexpression is linked to increased mutation frequency, but the underlying mechanisms affecting DNA repair remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms by which miR-155 overexpression drives genomic instability and increases mutation frequency.
• To investigate the impact of miR-155 on DNA repair pathways and identify its molecular targets.

Main Methods:

• Assessed mutation frequency in vitro and in vivo following miR-155 overexpression.
• Analyzed DNA repair pathway alterations, including homologous recombination and nonhomologous end-joining.
• Investigated the expression levels of DNA repair factors and polymerase delta subunits.
• Examined the role of FOXO3a in regulating polymerase delta expression.

Main Results:

• miR-155 overexpression significantly increased mutation frequency and promoted genomic instability.
• A decrease in homologous recombination and a concurrent increase in nonhomologous end-joining were observed.
• Downregulation of all four subunits of polymerase delta at the mRNA level was identified.
• FOXO3a was confirmed as a regulator of polymerase delta expression, with its suppression by miR-155 impacting POLD1 protein levels.

Conclusions:

• miR-155 overexpression elevates mutation frequency through a complex interplay with DNA damage response and repair pathways.
• The findings highlight miR-155's role in promoting genomic instability by modulating key DNA repair mechanisms and polymerase delta expression via FOXO3a.