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.

Keywords: DNA damage; DNA repair; oxidative stress; ultraviolet; xeroderma pigmentosum.

Figure 1

Human chromosomal location and general description of the genes encoding proteins involved in nucleotide excision repair (NER) and translesion synthesis (TLS). Mutations in these genes cause human syndromes, listed in the table.

Figure 2

Schematic representation of nucleotide excision repair (NER): the proteins associated with human diseases are highlighted. The downstream NER pathway and each of the sub-pathways (GGR and TCR) for lesion recognition are indicated, showing the different steps for DNA lesion removal in an error-free manner.

Figure 3

Schematic representation of translesion synthesis (TLS) by Pol η. The replication fork is blocked by DNA damage, and after a series of events (including the monoubiquitination of PCNA), a polymerase switch provides DNA polymerase eta (XP-V) with an opportunity to bypass the lesion. In this figure, only one strand (leading strand) is represented. At the end of the process the lesion remains in the DNA, but the replication of this molecule can proceed.

Figure 4

The consequences of DNA damage and how defective NER and TLS may explain certain clinical phenotypes. Different types of DNA damage can be induced by a variety of endogenous and exogenous agents. NER removes several of these lesions and TLS helps to replicate them, aiming maintenance of the genome stability, and guaranteeing normal cell proliferation, and normal human life (represented in green). When these mechanisms fail, errors in DNA replication increase mutagenesis and genetic instability, resulting in higher photosensitivity (observed in UVSS and XP patients) and risk of cancer development (observed in XP patients). Defective GGR-NER and TLS better explain these phenotypes (in red, superior part of the figure). Alternatively, endogenous DNA damage (including those induced by ROS) may disturb the transcription and/or cause replication blockage, leading to cell death, thus defective TCR-NER better explain the more severe phenotypes (including premature aging) of XP/CS, CS and other syndromes. Other effects, such as impaired transcription or damaged mitochondria may also be involved in these phenotypes (in red lower part of the figure).

Figure 5

Strategies for molecular diagnosis of XP patients. Identification of XP gene mutation based on a series of biological and biochemical assays using primary cells obtained from patient skin biopsies. Although the information from these cells has always been rich, the direct sequencing of DNA repair genes using next generation sequencing techniques may facilitate the molecular diagnosis using blood or saliva samples.