Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency

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Accumulation of DNA damage has been implicated in aging. Many premature aging syndromes are due to defective DNA repair systems. The endonuclease XPG is involved in repair of helix-distorting DNA lesions, and XPG defects cause the cancer-prone condition xeroderma pigmentosum (XP) alone or combined with the severe neurodevelopmental progeroid disorder Cockayne syndrome (CS). Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid background- displays many progressive progeroid features, including early cessation of growth, cachexia, kyphosis, osteoporosis, neurodegeneration, liver aging, retinal degeneration, and reduced lifespan. In a constitutive mutant with a complex phenotype it is difficult to dissect cause and consequence. We have therefore generated liver- and forebrain-specific Xpg mutants and demonstrate that they exhibit progressive anisokaryosis and neurodegeneration, respectively, indicating that a cell-intrinsic repair defect in neurons can account for neuronal degeneration. These findings strengthen the link between DNA damage and the complex process of aging.

Vyšlo v časopise: Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004686
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004686

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