MITOCHONDRIAL TARGETING OF HUMAN DNA GLYCOSYLASES FOR REPAIR OF OXIDATIVE DNA-DAMAGE

Oxidative damage to mitochondrial DNA has been implicated in human deg enerative diseases and aging, Although removal of oxidative lesions fr om mitochondrial DNA occurs, the responsible DNA repair enzymes are po orly understood, By expressing the epitope-tagged proteins in COS-7 ce lls, we examined subcellular localizations of gene products of human D NA glycosylases: hOGG1, hMYH and hNTH1. A gene encoding for hOGG1 whic h excises 7,8-dihydro-8-oxo-guanine (8-oxoG) from DNA generates four i soforms by alternative splicing (types 1a, 1b, 1c and 2), Three tagged isoforms (types Ib, Ic and 2) were localized in the mitochondria, Typ e la protein, which exclusively contains a putative nuclear localizati on signal, was sorted to the nucleus and lesser amount to the mitochon dria, hMYH, a human homolog gene product of Escherichia coli mutY was mainly transported into the mitochondria, hNTH1 protein excising sever al pyrimidine lesions was transported into both the nucleus and mitoch ondria, In contrast to the three DNA glycosylases, translocation of th e human major AP endonuclease (hAPE) into the mitochondria was hardly observed in COS-7 cells, These results suggest that the previously obs erved removal of oxidative base lesions in mitochondrial DNA is initia ted by the above DNA glycosylases.