Nucleotide Excision Repair in Cancer, Ageing and Stress Resistance
(Nucleotide excisie herstel in kanker, veroudering en stress resistentie)
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The genetic information that takes care of the proper functioning of all cell types that makes up an organism is organized in DNA. This so-called blue print of life is continuously attacked by a variety of genotoxic agents and environmental stresses that can damage the DNA (Figure 1). For instance, ultraviolet radiation (UV) causes helix-distorting lesions, cis-syn-cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone products (6-4PPs) (Sancar, 1996). On the other hand, ionizing radiation (IR) can cause formation of single strand breaks (SSBs) and double strand breaks (DSBs) (van Gent et al., 2001). The organism’s own metabolism generates reactive oxygen species (ROS) (including superoxide anions, hydrogen peroxide and hydroxyl radicals and their numerous subsequent reaction products) lipid peroxidation products, oestrogen metabolites, reactive carbonyl species, endogenous alkylating agents, spontaneous hydrolysis and deamination products (De Bont and van Larebeke, 2004). These result in DNA damages like oxidative DNA lesions, including 8-oxo-2’-deoxyguanosine (oxodG), thymine glycols, cyclopurines and SSBs and DSBs (Hoeijmakers, 2001). Finally, spontaneous modifications of nucleotides such as hydrolysis leading to abasic sites are common in cells. In total this adds up to 104-105 lesions per cell per day (Lindahl, 1993). The consequences of DNA damage can be severe and may lead to cellular malfunctioning caused by hampered transcription and replication, and may result in permanent cell cycle arrest (senescence) or cell death (apoptosis). If the cells don’t get replaced, and the tissue or organismal homeostasis gets lost, it can result in (premature) ageing (Mitchell et al., 2003). However, when these DNA damages result in irreversible mutations or chromosomal aberrations, and therefore replication errors, these mutations can lead to carcinogenesis (Mitchell et al., A complex network of DNA repair pathways (first found in bacteria and yeast), each selective for a specific subset of DNA lesions has evolved to overcome early onset of cancer or ageing. However, the more complex the system, the more sensitive it is to errors and deficiencies.
Het onderzoek is financieel gesteund door het ZonMw programma RIDE. Bijdragen in de drukkosten zijn verkregen van de J.E. Jurriaanse Stichting te Rotterdam, HemoCue Diagnostics B.V. te Waalre en Greiner bio-one te Alphen a/d Rijn.
- ischemia reperfusion injury
- dna repair