Cell and tissue responses to genotoxic stress

Abstract

Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins

“…The fact that AR appears highly heritable in humans is consistent with a body of research in rodents that demonstrates significant strain differences in DNA-damage-induced apoptosis in various tissues (for a review see Coates et al, 2005). The reduced AR seen in some mouse strains such as DBA/2 has been correlated with an increased incidence of genetic defects in irradiated cells (Watson et al, 1997;Wallace et al, 2001).…”

Genotoxic damage in polychaetes: A study of species and cell-type sensitivities

“…Significant relationships between DNA damage and the antioxidant status [35] and repair capacity of cells [36] have been shown to account for cellular and tissue specific differences in genotoxic responses within human cell lines [36,37]. Any differences in defence or repair capabilities of polychaete coelomocytes are likely to be related to the different functional roles of these cells.…”

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…Second, if the DNA repair mechanism of the cell is compromised, then the accumulation of multiple genetic mutations may occur. The consequence of the accumulation of mutations in a susceptible cell may lead to the perturbation of regulatory network(s) that controls proliferation, survival, cellular function and ultimately results in cancer (Coates et al, 2005). Many of the cigarette smoke carcinogens are well-known initiators and promoters of carcinogenesis in various organs such as the lung, oropharynx, stomach, pancreas, liver and colon (Nishikawa et al, 2004).…”