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Cancer and Aging in DNA repair deficiency: cause and treatment
Author(s) -
Niedernhofer Laura J.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.429.1
Subject(s) - dna repair , dna damage , nucleotide excision repair , cancer , ercc1 , premature aging , cancer research , neurodegeneration , biology , medicine , pathology , genetics , dna , disease
Inherited mutations in genes required for DNA repair or the cellular response to DNA damage lead to a variety of diseases characterized by accelerated aging and/or an increased risk of cancer. Studies in mouse models of these diseases revealed a strong correlation in the molecular mechanisms and pathogenesis between these progeroid syndromes and natural aging. This provides evidence that DNA damage can play a causal role in aging. We created mice that express 10% of the normal level of ERCC1‐XPF endonuclease, an enzyme that participates in nucleotide excision repair, interstrand crosslink repair and double‐strand break repair. Beginning at 8 wks of life, the mice show spontaneous and progressive symptoms associated with aging including neurodegeneration, muscle wasting, loss of vision and hearing, urinary incontinence, epidermal atrophy, bone marrow failure, decreased liver and kidney function, osteoporosis and intervertebral disc degeneration. In contrast, mice expressing 30% of the normal level of ERCC1‐XPF have a very high incidence of cancer. These mice offer a model system for identifying the mechanism by which DNA damage can drive degenerative changes associated with aging as well as cancer. Currently, we are treating the mice with stem cells, radical scavengers and inhibitors of apoptosis to determine the underlying mechanism of how DNA damage promotes aging and age‐related diseases.