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Chair(s): Mitra, Sankar
(SY001) Repair of oxidative damage in the mammalian genome: a complex picture.
Mitra, Sankar*,1, Dou, Hong1, Wiederhold, Lee1, Mokkapati, Sanath1, Chattopadhyay, Ranajoy1, Bhakat, Kishor1, Hazra, Tapas1, 1 Sealy Center for Molecular Science, Galveston, TX, USA
ABSTRACT- Oxidatively damaged bases, and abasic (AP) sites and their cleavage products, induced by reactive oxygen species (ROS) and ionizing radiation, are repaired via the DNA base excision repair (BER) pathway. Previously characterized mammalian DNA glycosylases, OGG1 and NTH1, excise the majority of oxidatively damaged bases. Two newly characterized human DNA glycosylases, NEIL1 and -2, are distinct from NTH1 and OGG1 in structural features and reaction mechanism, but act on many common substrates. Both groups of glycosylases have intrinsic abasic (AP) lyase activity for cleaving DNA at AP sites. OGG1 and NTH1 generate 3′ phosphodeoxysugar terminus while NEILs, which are uniquely active with bubble DNA, produce 3′ phosphate. In E. coli, AP-endoncuelases (APEs) remove both types of 3 ′blocking groups. In mammalian cells, APE1, the only APE, removes the 3 ′ phosphosugar residues while polynucleotide kinase is responsible for removing the 3 ′phosphate. We have suggested that NEILs function in repair of base lesions during replication and/or transcription. We have shown that S-phase-specific NEIL1 interacts with PCNA which stimulates NEIL1 but not NEIL2, suggesting NEIL1's involvement in replication-associated repair (RAR). In contrast, NEIL2's stable association with RNA polymerase II suggests its involvement in transcription-coupled repair. Thus NEILs may act in maintaining the functional integrity, while OGG1/NTH1 are needed for maintaining global integrity of mammalian genomes. Repair of AP sites and their oxidation products, endogenously generated by ROS, requires APE1 which is essential in mouse embryo, unlike in bacteria or yeast. We have generated APE1 conditional mutants of mouse embryo fibroblasts (MEF), and showed that inactivation of APE1 induces apoptosis. The essential function of APE1 in vivo may be in repair of oxidized AP sites which could not be repaired via the alternative, APE1-independent BER pathway. [Research supported by NIH grants CA81063, ES08457, CA53791 and AG021830 (SM) and CA102271 (TKH)].
Key words: base excision repair, oxidative DNA damage, DNA glycosylases, AP-endonuclease (APE)
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