ty for coumarin and all of which also showed significantly higher IC50 values for 8-MOP in coumarin oxidation. In support of these in vitro data, our molecular docking study has also showed that the mutations have induced enlarged active site cavity in CYP2A615, CYP2A621 and CYP2A622 and loss of H bond between 8-MOP and active site residue Asn297 in all mutants. All these data indicate that structural changes induced by the mutations at different sequence locality have altered ligand binding within the CYP2A6 active site. BER corrects a broad spectrum of DNA lesions caused by reactive oxygen species and alkylating agents that would otherwise result in point mutations. The damaged nucleotide is first recognized by one of many DNA damage specific glycosylases. For example 8-oxoguanosine-glycosylase 1 is the primary glycosylase to excise the major ROS-induced base lesion, 8-oxoG. Glycosylases remove the damaged base to generate an apurinic/apyrimidinic site. AP endonuclease 1 then makes a nick 59 to the AP site, generating a dRP intermediate and a one base gap. DNA Polymerase b then fills in the missing nucleotide while its lyase activity generates a 59 phosphorylated DNA strand by excising the 59 terminal dRP residue so that DNA ligase can repair the nick. BER also repairs DNA single strand breaks that form spontaneously at AP sites, as a DNA repair intermediate or after exposure to ROS. XRCC1 is critical for repairing SSBs by interacting with 
a number of BER proteins including APE1,, and PARP-1. Thus, deletion of BER components disables the repair of base lesions, AP sites and SSBs. 1 Deletion of Ku Interferes with AP Site Repair By contrast PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19650698 NHEJ repairs DNA DSBs. To initiate NHEJ, Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA-PKCS. Cells deleted for any of these proteins CF-101 chemical information exhibited telomere end fusion, hypersensitivity to clastogenic agents, and premature replicative senescence. Mice deleted for these proteins exhibited premature aging. Thus, deletion of Ku70, Ku80 or DNA-PKCS resulted in a similar phenotype demonstrating a common defect in the holoenzyme. In addition, XRCC4 and DNA ligase IV form a heterodimer to join the broken ends. Cells deleted for either of these proteins also exhibited hypersensitivity to clastogens, premature replicative senescence and early aging. Thus, deletion of NHEJ proteins caused a similar phenotype. However, our data also show that cells deleted for either Ku70 or Ku80 exhibited an NHEJ-independent phenotype. We found cells deleted for Ku70 or Ku80 were hypersensitive to ROS and alkylating agents implicating defective BER. However, cells deleted for Lig4 did not exhibit these hypersensitivities exonerating defective NHEJ. In addition, extracts from cells deleted for Ku80, but not Lig4, exhibited reduced BER capacity. Furthermore, ectopic expression of OGG1 or PARP-1 in Ku80-deleted cells rescued hypersensitivity to ROS suggesting Ku80 deletion disabled BER. These data suggested Ku80-deletion caused a BER defect that was unrelated to NHEJ. We hypothesized that free Ku70 and free Ku80 could influence BER. Cells deleted for either Ku70 or Ku80 did not exhibit the same sensitivity to ROS agents and extracts from cells deleted for Ku80, but not Ku70, exhibited reduced BER capacity . We further hypothesized that free Ku70 could have activity in ku80-/- cells and free Ku80 could have activity in ku70-/- cells. This is possible since some Ku80 remains in the absence of Ku70 and vice
