plays a major role in carrying out the initial pairing reaction during homologous recombination, and dense complexes can be detected in the nuclei of irradiated cells (Haaf and others 1995), which are thought to be part of the homologous rejoining complexes (Scully and others 1997b; Scully and others 1997a). Rad51 is inhibited by association with the tumor suppressor p53 (Buchhop and others 1997) and interacts with the breast-cancer-specific gene products Brcal and Brca2 (Scully and others 1997b; Scully 1997a). Knockout of the Rad51 and the Brcal and Brca2 genes result in early embryo death (Lim and Hasty 1996; Tsuzuki and others 1996); this suggests a complex regulatory scheme for homologous recombination during development and carcinogenesis.

The nonhomologous recombination pathway for repair of radiation-induced DNA breakage in somatic cells involves an end-to-end rejoining reaction in which broken ends of DNA are braced by a set of supporting proteins. The gap between DNA ends is bridged by overlapping single-strand termini that are usually less than 10 nucleotides long (more commonly one to five long) and a set of proteins, including Ku70, and Ku86, p450 kinase, and DNA ligase IV (Kirchgessner and others 1995; Lees-Miller and others 1995; Getts and Stamato 1994; Rathmell and Chu 1994; Smider and others 1994; Taccioli and others 1994; Anderson 1993) (figure 6.3). The p450 kinase interacts with p53, the major signaling protein that regulates cell-cycle control, apoptosis, and the transcription of many downstream genes (Elledge and Lee 1995; Kastan and others 1995; Lane 1993). Defects in p450 have been associated with the systemic combined immunodeficiency (scid) phenotype in mice (Kirchgessner and others 1995). Knockout of the Ku70 and Ku86 genes renders cells more sensitive to ionizing radiation but, unlike the genes involved in homologous recombination, does not result in embryo death.

The rejoining reaction results in a junction made by an overlap of a few bases at each terminus with additional possibilities of single-base or larger insertions, deletions, or mismatches. No consistent DNA-sequence motifs have been found in these short regions of sequence overlaps, despite direct investigation of micro-satellite repeats and telomere and triplet repeat sequences. Insertions can be many kilobases long and can come from locally produced fragments or from single-strand invasion into proximal regions of DNA. The ends involved in rejoining reactions are not necessarily those from either side of the initial break but can be from other breaks made by the same alpha track. The intervening stretch of DNA can then be lost, with consequent chromosomal rearrangement. These losses and rearrangements can involve many kilobases of DNA, producing the losses, deletions, and rearrangements of genetic material which are hallmarks of genetic effects caused by densely ionizing radiation (Zhu and others 1996; Kronenberg and others 1995; Nelson and others 1994; Phillips and Morgan 1994). The process of DNA breakage and rejoining therefore initiates a major change in signal transduction and cellular regulation that can persist over many cell generations (see discussion of genetic instability below).



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