Analysis of Alterations in a Base-Excision Repair Gene in Lung Cancer

Cellular DNA is continuously exposed to a variety of insults induced by different endogenous or exogenous agents, including ionizing radiation, ultraviolet (UV) light, chemicals, and by-products of oxidative stress (1). Damaged DNA, if not repaired, can cause cell death, aging and cancer. Therefore, a highly efficient network of DNA repair systems is necessary to remove DNA lesions and to restore and maintain the correct genetic information. DNA lesions can be repaired by three major pathways ( see Fig. 1) : a) a direct reversal pathway, which undoes a harmful reaction and restores the original DNA by transferring a methyl group from O 6 -methylguanine by O 6 -Methylguanine-DNA methyltransferase ( 2) ; b) an excision-repair pathway, which involves the removal of the endogenous damaged DNA; and c) a postreplication pathway, which allows cells to complete the replication process without removing the lesion. There are three major categories of excision repair ( see Fig. 1) : the nucleotide-excision repair (NER) pathway, the base-excision repair (BER) pathway, and the mismatch-repair (MMR) pathway ( 3 - 9) . Which of these is used depends on their mechanism of repair and the nature of the damaged substrate. The NER pathway can repair a 25-32 bp lesion ( 5 , 9) , whereas the BER pathway repairs a short patch (1-14 bp) of altered bases ( 10) . Mismatch repair is responsible for removing mis-paired DNA sequences and involves excision of a long, single-stranded fragment spanning the mismatch, with resynthesis of the segment ( 9) . Schematic representation of the different pathways of DNA repair. Human Mut S homolog 2, hMSH2; Human Mut L homolog 1, hMLH1; human postmeoitic segregation 2, hPMS2; G/T binding protein, GTBP; Proliferating Cell Nuclear Antigen, PCNA; X-Ray Cross Complementing 1, XRCC1, Xeroderma Pigmentosum, XP; Base-excision repair, BER; Nucleotide excision repair, NER. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.