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ERCC1-deficient cells and mice are hypersensitive to lipid peroxidation

Czerwińska, Jolanta and Nowak, Małgorzata and Wojtczak, Patrycja and Dziuban-Lech, Dorota and Cieśla, Jarosław M. and Kołata, Daria and Gajewska, Beata and Barańczyk-Kuźma, Anna and Robinson, Andria R. and Shane, Hillary L. and Gregg, Siobhán Q. and Rigatti, Lora H. and Yousefzadeh, Matt J. and Gurkar, Aditi U. and McGowan, Sara J. and Kosicki, Konrad and Bednarek, Małgorzata and Zarakowska, Ewelina and Gackowski, Daniel and Oliński, Ryszard and Speina, Elzbieta and Niedernhofer, Laura J. and Tudek, Barbara (2018) ERCC1-deficient cells and mice are hypersensitive to lipid peroxidation. Free Radical Biology & Medicine, 124 . pp. 79-96.

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Lipid peroxidation (LPO) products are relatively stable and abundant metabolites, which accumulate in tissues of mammals with aging, being able to modify all cellular nucleophiles, creating protein and DNA adducts including crosslinks. Here, we used cells and mice deficient in the ERCC1-XPF endonuclease required for nucleotide excision repair and the repair of DNA interstrand crosslinks to ask if specifically LPO-induced DNA damage contributes to loss of cell and tissue homeostasis. Ercc1-/- mouse embryonic fibroblasts were more sensitive than wild-type (WT) cells to the LPO products: 4-hydroxy-2-nonenal (HNE), crotonaldehyde and malondialdehyde. ERCC1-XPF hypomorphic mice were hypersensitive to CCl4 and a diet rich in polyunsaturated fatty acids, two potent inducers of endogenous LPO. To gain insight into the mechanism of how LPO influences DNA repair-deficient cells, we measured the impact of the major endogenous LPO product, HNE, on WT and Ercc1-/- cells. HNE inhibited proliferation, stimulated ROS and LPO formation, induced DNA base damage, strand breaks, error-prone translesion DNA synthesis and cellular senescence much more potently in Ercc1-/- cells than in DNA repair-competent control cells. HNE also deregulated base excision repair and energy production pathways. Our observations that ERCC1-deficient cells and mice are hypersensitive to LPO implicates LPO-induced DNA damage in contributing to cellular demise and tissue degeneration, notably even when the source of LPO is dietary polyunsaturated fats.

Item Type:Article
Subjects:Q Science > Q Science (General)
ID Code:1542
Deposited By: MSc Jolanta Czerwińska
Deposited On:11 Jun 2018 10:34
Last Modified:02 Jun 2019 22:05

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