ERCC1-deficient cells and mice are hypersensitive to lipid peroxidation

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Lipid peroxidation (LPO) products accumulate with aging, forming DNA adducts and crosslinks.
• The ERCC1-XPF endonuclease is crucial for nucleotide excision repair and DNA interstrand crosslink repair.

Purpose of the Study:

• To investigate if LPO-induced DNA damage contributes to loss of cell and tissue homeostasis.
• To determine the impact of LPO on DNA repair-deficient cells and mice.

Main Methods:

• Utilized ERCC1-XPF deficient cells and mice.
• Exposed cells and mice to LPO products (HNE, crotonaldehyde, malondialdehyde) and LPO inducers (CCl4, polyunsaturated fatty acids).
• Assessed cellular proliferation, ROS production, DNA damage, DNA repair pathways, and energy production.

Main Results:

• ERCC1-XPF deficient cells and mice showed hypersensitivity to LPO products and inducers.
• 4-hydroxy-2-nonenal (HNE) inhibited proliferation, increased ROS and LPO, induced DNA damage, and promoted senescence more in ERCC1-deficient cells.
• HNE deregulated base excision repair and energy production pathways in ERCC1-deficient cells.

Conclusions:

• LPO-induced DNA damage contributes to cellular demise and tissue degeneration, especially in ERCC1-deficient contexts.
• ERCC1-XPF deficiency exacerbates cellular and tissue damage caused by LPO.
• Dietary polyunsaturated fats can be a source of LPO-induced DNA damage contributing to degeneration.