through many kilobases to cytogenetically visible chromosomal changes (Sankaranarayanan 1991). Chromosomal fragments that are not rejoined can be excluded from interphase nuclei and can form micronuclei. These micronuclei, which encapsulate p53 (Unger and others 1994) can be scored as a quantitative measure of chromosomal damage in somatic and cultured cells. The size of deletions that persist in surviving cells is determined by the initial spacing of DNA double-strand breaks and by the presence of vital genes in the intervening sequences. Deletion sizes associated with loss of function of the adenine phosphoribosyl transferase (APRT) gene, for example, are generally smaller than those associated with loss of function of the hypoxanthine phosphoribosyl transferase (HPRT) gene because of the presence of vital genes closer to APRT than HPRT (Park and others 1995; Nelson and others 1994; Fuscoe and others 1992; Morgan and others 1990; Thompson and Fong 1980). Deletion sizes and junction positions are markedly nonrandom in both the chromosomal HPRT gene and in episomal vectors that carry reporter genes. The positions of DNA breaks and the efficiency and precision of their repair are therefore strongly influenced by chromatin structure and attachment of DNA to nucleosomal and matrix proteins and the functions of flanking genes. In an experimental cell-culture system in which a single human chromosome bearing a marker gene is carried in a hamster cell line (the AL cell line), very few of the human genes are required for cell survival, and alpha-particle damage can produce very large deletions that involve most of the chromosome (Hei and others 1997; Ueno and others 1996). This situation cannot apply to most chromosomes in a normal cell, in which deletion sizes consistent with survival will be limited by the presence of important genes distributed throughout the genome.
One gene product, the p53 protein (figure 6.1), plays a critical role in regulating the multitude of responses that are elicited in damaged cells, especially those involving cell-cycle arrest and apoptosis, and interacts with numerous other regulatory and repair proteins (Elledge and Lee 1995; Kastan and others 1995; Lane 1993; 1992). The p53 protein is a rapidly synthesized, but short-lived, multifunctional protein which interacts with a wide array of other cellular and viral proteins and binds to DNA in both sequence-specific and sequence-independent fashions. In the presence of damage (either DNA breaks or reactive oxygen intermediates) the lifetime of p53 increases, it is phosphorylated at specific sites that depend on the particular signal, and it acts as a transcriptional activator with downstream effects on many other genes, especially stimulating transcription of p21, which then inhibits cell-cycle progression. Alpha-particle irradiation at low exposures has been shown to result in p53 stabilization in more cells than could have experienced alpha-particle tracks: this suggests that reactive oxygen intermedi-