The ion pairs that do not directly damage DNA can produce reactive oxygen intermediates. These intermediates influence the stability of p53 with downstream effects on cell regulation and can activate many cellular systems that are sensitive to the redox state of the cell, such as the fos/jun transcriptional regulators (Xanthoudakis and others 1996). Reactive oxygen intermediates can produce oxidative damage, of which 8-oxy-guanine is a major product. Oxidations are produced in DNA and in both deoxyribose and ribose triphosphates. Oxidized nucleotides can be incorporated into DNA and RNA, and lead to either DNA mutations or transcription and translation errors. Oxidized nucleotides can be eliminated from the nucleotide pool by MutT, which hydrolyzes 8-oxo-dGTP and 8-oxo-rGTP to monophosphates, thereby removing the oxidized bases from the pool of DNA and RNA precursors (Taddei and others 1997). MutT activity reduces mutations from naturally occurring oxidative reactions by a factor of about 104.
Oxidative damage involves production of damaged individual bases, such as 8-oxy-G, and many other products in DNA that cause point mutations by mispairing during DNA replication (Singer 1996) and that are repaired by the base-excision repair system. Base excision involves a set of glycosylases with limited ranges of substrate specificity (uracil, 3-methyladenine, formamidopyrimidine, glycosylases and others). The glycosylases remove damaged bases (Cunningham 1997; Singer and Hang 1997), leaving apurinic sites that are later cleaved by apurinic endonuclease (Hang and others 1996), and the gaps are replaced by polymerase β and completed by ligase I or III (Sancar and Sancar 1988). Several base-excision repair enzymes have multiple additional functions: the AP endonuclease is also known as Ref-1 and reduces the oxidized transcriptional regulators fos/jun (Xanthoudakis and others 1996); and pol β and ligase III are linked by structural protein XRCC1, which interacts with poly (ADP-ribose) polymerase (PARP) (Caldecott and others 1994). PARP is a major chromatin protein that is activated by DNA strand breaks and can exhaust the cellular NAD content by polymerization and hydrolysis (Cleaver and Morgan 1991).
DNA breaks and other base damage therefore are the assembly points for complex, multifunctional, multipurpose structures that signal their presence to many other cellular processes and within which repair and genetic changes occur. The combined actions of these cellular caretakers produces surviving cells that bear the permanent marks of alpha particle exposure, including deletions, insertions, amplifications, point mutations, and altered cellular regulation (Kronenberg and others 1995; Kronenberg 1994).
The end result of DNA breakage and rejoining is the deletion, insertion or rearrangement of various amounts of genetic material, from a few base pairs