Review Cytotoxicity and mutagenicity of endogenous DNA base lesions as potential cause of human aging Mansour Akbari *, Hans E. Krokan Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7006 Trondheim, Norway 1. Introduction At the cellular level, aging can be described as gradual changes in the molecular physiology of the cell that causes a decline in the normal function of cells. Several hypotheses on the mechanisms of aging have been developed, and they may not be uniform in all cells and organs. Common to most aging models is the idea that gradual change in the original structure of DNA is a major underlying cause. The somatic mutation theory of aging proposes that aging is due to accumulation of mutations in DNA in somatic cells over time (Kirkwood, 2005). However, whether such mutations accumulate at sufficient rate to be a major contributor to aging is uncertain (Hoeijmakers, 2007). Results from a number of studies, however, suggest that accumulation of DNA damage over time may cause a gradual decline in cellular function and manifestation of aging (Izzotti et al., 1999; Lu et al., 2004; Mecocci et al., 1999; Siomek et al., 2007). It is worth noticing the difference between mutation and DNA damage because these terms are occasionally confused in the literature. DNA damage includes any change to the chemistry of DNA, as well as chemically correct but inappropriate nucleotides which can be incorporated during DNA replication. Cells have evolved various repair mechanisms, each usually involving a number of proteins for detection and repair of damaged DNA (Krokan et al., 2004). DNA lesions can be converted to mutations upon DNA replication, thus changing the original nucleotide sequence of DNA. Mutations include single base substitutions and deletions, insertions and translocations. Once fixed as mutation in DNA such changes are undetectable by DNA repair systems. The present review focuses on endogenous DNA base damage and base repair, and the possible role of such damage in aging. 2. Types of DNA damage DNA is susceptible to damage from environmental sources like ultraviolet light and endogenous sources such as by-products of normal cellular metabolism, respectively. DNA lesions from endogenous factors include various types of base damage and single-strand breaks. DNA damage displays varying degrees of mutagenicity and toxicity depending on the type of damage (Table 1), the location of the lesion in the genome (promoter region, introns, exons or the transcribed strand of active genes), as well as the cell cycle and type of cell. Generally, DNA damage is also cytotoxic, due to interference with transcription and replication (Table 1). On the other hand, some strongly mutagenic lesions, e.g. uracil in a U:G context, do not necessarily impede processes of DNA metabolism, but may cause mutation with 100% efficiency during replication. Cells have evolved DNA damage response networks that control cell division and coordinate repair. If the damage persists these responses may trigger apoptosis to avoid transmis- sion of genetic errors from one cell to its progeny (Zhou and Elledge, 2000). Generally, the contribution of different types of DNA damage to cytotoxicity will depend on the number of lesions (Bennett et al., 1993), their ability to block replication (Yang and Mechanisms of Ageing and Development 129 (2008) 353–365 ARTICLE INFO Article history: Available online 12 February 2008 Keywords: Base excision repair Endogenous DNA damage Aging Reactive oxygen species Oxidative DNA damage ABSTRACT Endogenous factors constitute a substantial source of damage to the genomic DNA. The type of damage includes a number of different base lesions and single- and double-strand breaks. Unrepaired DNA damage can give rise to mutations and may cause cell death. A number of studies have demonstrated an association between aging and the accumulation of DNA damage. This may be attributed to reduced DNA repair with age, although this is apparently not a general feature for all types of damage and repair mechanisms. Therefore, detailed studies that improve our knowledge of DNA repair systems as well as mutagenic and toxic effects of DNA lesions will help us to gain a better insight into the mechanisms of aging. The aim of this review is to provide a brief description of cytotoxic and mutagenic endogenous DNA lesions that are mainly repaired by base excision repair and single-strand break repair pathways and to discuss the potential role of DNA lesions and DNA repair dysfunction in the onset of human aging. ß 2008 Elsevier Ireland Ltd. All rights reserved. * Corresponding author. Tel.: +47 72573073; fax: +47 72576400. E-mail address: mansour.akbari@ntnu.no (M. Akbari). Contents lists available at ScienceDirect Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev 0047-6374/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2008.01.007