DNA repair diseases: what do they tell us about cancer and aging?

Abstract

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.

Ageing as an Important Risk Factor for Cancer

“…Diseases such as xeroderma pigmentosum, Werner syndrome, Lynch syndrome and Fanconi anemia can be considered paradigmatic examples. Association of these rare diseases with untimely occurring malignant tumors was the leading motif in their initial clinical description (30,(46)(47)(48)(49)(50).…”

ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways

“…Defects in any of these pathways can lead to the rare hereditary disorder xeroderma pigmentosum (XP), characterized by extreme sun sensitivity and increased risk of skin cancer. Whereas the seven classical complementation groups (XP-A to XP-G) exhibit defective NER, the XP variant group (XP-V) results from mutations in the TLS DNA polymerase g (DiGiovanna and Kraemer, 2012, Menck andMunford, 2014).…”

Theories of Human Aging of Molecules to Society

“…Genetic manipulations of DNA repair in mice support this view and indicate that the commitment of specific pathways such as repair and nucleotide excision of nonhomologous end joining is associated with premature aging phenotypes [88]. In humans, it has been discovered that there are associated with defects in DNA repair and signs of premature aging as the xeroderma pigmentosum, skin cancer and progeroid syndromes [91] diseases. Critics of theories of wear and tear pose, however, that aging is not from a physical expectation but evolutionary.…”