RESPONSE TO DNA DAMAGE AND OXIDATIVE STRESS DURING CELLULAR AGING

氧化应激和DNA损伤在发育过程中起关键作用

Oxidative stress and DNA damage play a critical role in the development of age-associated degenerative diseases, and may underlie the aging process itself. Since cells respond to DNA damaging agents with the induction of various genes encoding proteins which are presumed to impart protection to the damaged cell, we initiated studies to examine whether the molecular response to DNA damage is altered as a function of aging. Normal differentiated cells undergo a finite number of divisions in culture before entering an irreversible state of growth arrest. This phenomenon, termed cellular senescence, is believed to reflect certain aspects of cellular aging in vivo. We have compared the expression of DNA-damage inducible genes in early passage and senescent WI-38 human lung fibroblasts. We have found that with cellular-aging there is a decline in the activation of activator protein 1 (AP-1) transcription factor complexes to a DNA-binding state in response to DNA damage. This reduced AP-1 binding activity is associated with reduced expression of collagenase, whose induction following UV radiation is mediated via an AP-1 binding element. Since AP-1 complexes are comprised of fos and jun proteins, both of which have been shown to be induced in response to DNA damage and oxidative stress, we examined whether fos and jun expression following DNA damage was altered with in vitro cellular aging. Comparison of early and late passage WI-38 fibroblasts showed no difference in the levels of expression of either c-fos or c-jun mRNA or protein in response to DNA damage. Thus, the reduced AP-1 binding activity seen in in vitro aging appears to reflect changes in posttranslational events leading to the activation of AP-1 complexes to a DNA-binding state. Like collagenase, many other DNA damage-inducible genes contain an AP-1 binding site which is presumed to play a role in mediating their expression in response to genotoxic stress. Thus, an age-related loss in AP-1 transcription factor complex activation could have a major impact on the cellular response to DNA damage.