Cytotoxicity and mutagenicity of endogenous DNA base lesions as potential cause of human aging (original) (raw)
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DNA damage, mutation and fine structure DNA repair in aging
Mutation Research/DNAging, 1995
The primary focus of this rcvicw ix on correlations found bctwcen DNA damage, repair. and aging. New techniques for the mcasurcmcnt of DNA damage and repair at the level of individual genes. in individual DNA strands and in individual nucleotides will allow us to gain information regarding the nature of these correlations. Fine structure studies of DNA damage and repair in specific regions, including active gents, telomeres, and mitochondria have begun. Considcrablc intragcnomic DNA repair hctcrogcncity has been found, and there have been indications of relationships between aging and repair in specific regions. More studies are necessary, however. particularly studies of the repair of cndogenous damage. It is emphasized that the information obtained must be viewed from a perspective that takes into account the total rcsponscs of the cell to damaging cvcnts and the interrelationships that exist bctuecn DNA repair and transcription.
DNA damage and repair in relation to aging
1989
Aangezien NiedermflUer bij-zijn experimenten hoge concentraties van DNA beschadigende agentia heeft gebruikt, is zijn conclusie dat het vermogen om bepaalde DNA-schades te herstellen afneemt met de leeftijd voorbarig.
Although the links between defects in DNA repair and cancer are well established, an accumulating body of evidence suggests a series of functional links between genome maintenance pathways, lifespan regulation mechanisms and age-related diseases in mammals. Indeed, the growing number of DNA repair-deficient patients with progeria suggests that persistent DNA damage and genome caretakers are tightly linked to lifespan regulating circuits and age-related diseases. Here, we discuss the impact of irreparable DNA damage events in mammalian physiology highlighting the relevance of DNA repair factors in mammalian development and aging. The Adverse Consequences of Genome Instability DNA damage is essentially random in nature, ubiquitous and unavoidable for most, if not all, living organisms. Moreover, the mammalian genome must be preserved for relatively long periods of time so that it is faithfully passed into the progeny. This, and the fact that DNA has an inherently vulnerable physicochemical stability, have pushed cells to evolve mechanisms to efficiently counteract DNA damage. Such mechanisms often involve a battery of programmed responses i.e. delicate DNA damage sensors, signaling cascades and overlapping DNA repair mechanisms that continuously scan the genome to detect DNA lesions, surmount a proper DNA damage response (DDR) and repair the myriads of (structural) DNA modifications
Premature aging and cancer in nucleotide excision repair-disorders
Dna Repair, 2011
During the past decades, the major impact of DNA damage on cancer as 'disease of the genes' has become abundantly apparent. In addition to cancer, recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair systems protect not only against cancer but also equally against to fast aging has become evident from a systematic, integral analysis of a variety of mouse mutants carrying defects in e.g. transcription-coupled repair with or without an additional impairment of global genome nucleotide excision repair and the corresponding segmental premature aging syndromes in human. A striking correlation between the degree of the DNA repair deficiency and the acceleration of specific progeroid symptoms has been discovered for those repair systems that primarily protect from the cytotoxic and cytostatic effects of DNA damage. These observations are explained from the perspective of nucleotide excision repair mouse mutant and human syndromes. However, similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging.
DNA repair diseases: what do they tell us about cancer and aging?
Genetics and Molecular Biology, 2014
The discovery of DNA repair defects in human syndromes, initially in xeroderma pigmentosum (XP) but later in many others, led to striking observations on the association of molecular defects and patients' clinical phenotypes. For example, patients with syndromes resulting from defective nucleotide excision repair (NER) or translesion synthesis (TLS) present high levels of skin cancer in areas exposed to sunlight. However, some defects in NER also lead to more severe symptoms, such as developmental and neurological impairment and signs of premature aging. Skin cancer in XP patients is clearly associated with increased mutagenesis and genomic instability, reflecting the defective repair of DNA lesions. By analogy, more severe symptoms observed in NER-defective patients have also been associated with defective repair, likely involving cell death after transcription blockage of damaged templates. Endogenously induced DNA lesions, particularly through oxidative stress, have been identified as responsible for these severe pathologies. However, this association is not that clear and alternative explanations have been proposed. Despite high levels of exposure to intense sunlight, patients from tropical countries receive little attention or care, which likely also reflects the lack of understanding of how DNA damage causes cancer and premature aging.