B DNA Damage

Certain types and/or levels of damage to genomic DNA can cause normal mammalian cells to undergo a senescence arrest. This damage may derive from endogenous or exogenous sources and includes DNA base and sugar modifications as well as single- or double-strand breaks in the DNA (19,20,24). Because telom-eric DNA appears to be repaired less efficiently than other parts of the genome (52,53), generalized genomic damage may cause telomeres to shorten (26,54) and/or malfunction. However, some types of damage—for example, oxidative damage caused by exposure to hydrogen peroxide—appear to induce the senescence response independent of an effect on telomeres (55). Moreover, deficiencies in any one of a number of components that participate in DNA repair can cause premature replicative senescence or a hypersensitive senescence response to DNA-damaging agents. Mammalian organisms (generally humans or mice) that are genetically deficient in DNA repair frequently are cancer prone and, in some cases, develop—prematurely—selected aging phenotypes (56-60).

The most striking example of the relationship between DNA damage and repair, cellular senescence, genomic instability, and aging is the Werner syndrome (WS). WS is caused by a deficiency in WRN (61), which encodes a DNA helicase (62) and exonuclease (63,64). WRN almost certainly participates in one or more major DNA repair pathway that is important for maintaining genomic stability (65-69). Cells derived from donors with WS undergo premature replicative senescence in culture (70), and donors with WS develop prematurely several phenotypes associated with aging, including cancer (57).

The senescence response to DNA damage may prevent the fixation of potentially oncogenic mutations in the genome. In addition, the senescence response prevents the proliferation of cells that harbor potentially cancer-causing mutations and, in particular, the proliferation of cells with lesions that can lead to chromosomal instability.

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