Transcriptional Functions of DNA Repair Proteins Involved in Premature Aging

Premature aging diseases or progerias are rare genetical disorders displaying symptoms of the aging body early in life or even in childhood. They are called segmental because they show some, but not all features of aging. There is the progeria of the adult, Werner syndrome and, more severe because limiting lifespan to the first or second decade, the progerias of the childhood, Cockayne syndrome, trichothiodystrophy and HutchinsonGilford syndrome. With the exception of Hutchinson-Gilford syndrome, the progerias are caused by recessive mutations. Cockayne syndrome and trichothiodystrophy are polygenic disordersthe recessive mutation in five respective three different genes can cause the same devastating phenotype. All genes of a polygenic disorder may function in a critical redundant pathway . The identification of these pathways is topic of intensive labour in different laboratories for more than one reason. First, the identification of the molecular defects will help us to treat these diseases. Second, as these diseases mimic the normal aging process, understanding these diseases will strengthen our understanding of aging in general. Third, as these disorders display accelerated aging, the underlying pathways may be critical for the rate of aging and may help us to slow aging respectively allow us to affect healthy aging. Aging is believed to be due to the accumulation of molecular and macromolecular damage (Kirkwood, 2010), thus accelerated aging might be caused by a higher damage rate or by an impairment of counteracting pathways as repair mechanisms. The later assumption is generally believed to be the explanation for the accelerated aging seen in progerias, defects in macromolecular repair pathways, especially in DNA-repair pathways are generally considered as being causal for accelerated aging. Although there is ample evidence that aging is accompanied by macromolecular damage and DNA damage in particular, the causal connection between DNA damage and tissue or organismal aging is far from understood. Here the investigation of progerias is able to fuel our understanding of the mechanisms of aging as most of the involved genes play roles in different DNA repair pathways. But it is not so simple because all the progeria genes display multiple functions in the cells and are also involved in the regulation of gene expression by acting as basal transcription factors or as chromatin modifying enzymes. The discovery of the transcriptional function of DNA repair factors was accompanied by the hypothesis that accelerated aging could also be caused by alterations in gene expression mechanisms (Drapkin et al, 1994, Guzder et al, 1994). Since then the “transcriptional” versus the “DNA