ࡱ> 685s jbjb 8kk] Q$,ui Q    ""   {bgLBase Excision Repair (BER) The most pro-active repair process is likely BER, a pathway that corrects DNA modifications that arise either spontaneously or from attack by reactive chemicals. In fact, it has been estimated that well over 10,000 assaults will take place on our DNA each day, with the most prominent offender being reactive oxygen species (superoxide, hydroxyl radical, and hydrogen peroxide), a.k.a. free radicals. These reactive chemicals are produced as natural by-products of food metabolism in the effort to generate energy, and can modify cell membranes, proteins, and DNA. Uncontrolled free radical activity, and ultimately the damage it produces, has been associated with cancer, aging, neurodegeneration, athritis, and other human diseases. BER is the primary defense system against the deleterious effects of most oxidative DNA damage. Moreover, BER is often responsible for correcting damages that arise spontenously, due to the inherent instability of DNA, or from alkylation of DNA. In all, BER copes with inappropriate bases (mismatched or damaged) that arise from replication errors or via chemical modification by oxidation or alkylation; sites of base loss that are formed by enzyme-catalyzed, spontaneous or mutagen-induced base release; and strand breaks that are products of free radical attack of DNA. Many of these same damages are generated by anti-cancer agents and environmental mutagens which generate free radicals (such as ionizing radiation and radiomimetic antibiotics). In essence, BER copes with those damages that are produced every day. BER involves the concerted effort of several repair proteins that recognize and excise specific DNA damages, eventually replacing the damaged moeity with a normal nucleotide and restoring the DNA back to its original state (Figure). Typically, the first step of BER involves the removal of an inappropriate base from DNA by a DNA glycosylase. Such DNA glycosylases bind specifically to a target base and hydrolyze the N-glycosylic bond, releasing the inappropriate base while keeping the DNA backbone intact. In humans, six DNA glycosylases have been identified, and each excises an overlapping subset of either spontaneously formed (e.g. hypoxanthine), oxidized (e.g. 8-oxo-7,8-dihydroguanine), alkylated (e.g. 3-methyladenine), or mismatched (e.g. T:G) bases. The abasic site (i.e. the site of base loss) that is formed by DNA glycosylase activity is subsequently recognized by Ape1 (the major AP endonuclease), which incises the phosphodiester backbone immediately 5' to the lesion leaving behind a strand break with a normal 3'-hydroxyl group and an abnormal 5'-abasic terminus. There have been reports that certain DNA glycosylases will communicate with Ape1 to facilitate the initial stages of the repair process. The primary pathway of BER (short-patch BER) then proceeds with DNA Pol) }dmei%Z臚R@mY@FL^x1 n0#Dk&9uե{JcJ ?6), -UX@@j'@# (WGȐݑV(b removing the 5'-abasic residue via its 5 -deoxyribose-phosphodiesterase activity and filling in the single nucleotide gap (Figure, pathway on left). To complete the process, the nick is sealed by DNA Ligase I or a complex of XRCC1 and LigIII. It is noteworthy that, in eukaryotes, an alternative BER pathway (Figure, pathway on right) exists that involves the replacement of more than a single nucleotide (~7 nucleotides) and requires the Fen1 protein to excise the flap-like structure that is produced by DNA polymerase strand displacement. This long-patch process may have evolved as a more efficient or redundant mechanism for the repair of 5'-termini (perhaps endonuclease-incised reduced or oxidized abasic sites) that are not substrates for the 5'-phosphodiesterase activity of Polb. The initial observation that this alternative pathway requires PCNA suggested the involvement of Pol( and Pold in BER. However, it was recently shown in reconstituted assays that Polb can carry out strand displacement and long patch repair synthesis in vitro, and that PCNA functions to stimulate FEN1 endonuclease activity. Thus, long-patch BER has been divided into two subpathways: (1) a PCNA-stimulated, Polb-directed pathway, and (2) a PCNA-dependent, Pold/(-directed pathway. The type of substrate encountered (i.e. the target damage or the form [circular or linear] of the DNA) likely dictates whether short-patch or either of the long-patch repair pathways is employed. Much of the current research in BER revolves around defining the biological contributions of the interactions within this pathway. Strikingly, in most cases, mice that are engineered to lack one of the BER components do not survive embryogenesis, suggesting an absolute requirement for this repair system in development. The likely interpretation is that BER is needed to cope with the every day accumulation of DNA damage, and that in its absence, the genome is damaged beyond compatibility with normal development. Alternatively, these proteins may serve yet unidentified roles in embryogenesis that are not repair related, but this seems unlikely given the similar results obtained with several different BER factors. In any case, BER is a vital process required for maintaining genetic integrity and for animal survival. The recent finding that the human 8-oxoguanine DNA glycosylase (OGG1) maps to a region associated with lung cancer is the first demonstration of a possible relationship of BER to a human cancer. It seems likely, that more subtle mutations within a BER gene that lead to a slightly reduced repair capacity, and not the absence of the repair system, are more likely to be associated with cellular dysfunction. by David M. Wilson III $   $ (9Q460BvxFJ 6OJQJ jeOJQJ CJOJQJ ;OJQJOJQJ >*OJQJOJQJ 5OJQJ)= K0dh = K / =!"#$%|HH(FG(HH(d'hyronemTyrone [(@(NormalCJmH <A@<Default Paragraph Font88   J=P\ > D n  ^ h = A  David Wilson2dmw iii:DMWIII:LLNL items:WebSite:Repair Group:BER David Wilson-dmw iii:Temporary Items:Word Work File A 3990 David Wilson-dmw iii:Temporary Items:Word Work File A 3790 David Wilson-dmw iii:Temporary Items:Word Work File A 3158 David Wilson-dmw iii:Temporary Items:Word Work File A 3958 David Wilson-dmw iii:Temporary Items:Word Work File A 3958 David Wilson)dmw iii:Temporary Items:Word Work File A David Wilson III1dmwiii:DMWIII:LLNL items:WebSite:Repair Group:BER@ $_  5 LM M MMMP@PP$@PPP0@GTimes New Roman5Symbol3 Arial9Palatino3Times"1hC(F;t,Fw/& &$0IBase Excision Repair (BER) David WilsonDavid Wilson III2An ^ dJ<ddd2d3 *U<2U h\ gD&oo[[[G55!!I&5Z h 2d7D&oo[["""55555/dF/@ss Wire Oct 26 1999 8:30AM Benchmark Tape Systems Raises the Bar On Price Performance With FAS368M SCSI Controller Chip From QLogic by Business Wire Oct 19 1999 8:06AM


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