Excision repair of DNA base damage

Abstract

Exposure of cells to exogenous physical and chemical agents can result in damage to the DNA bases. DNA damage can lead to mutation, malignant transformation and cell death and may possibly be involved in cellular aging. Structurally related base modifications are expected to have similar biological effects regardless of the agent responsible for their formation. The biological effects may be a consequence of the local distortion of the DNA conformation by the lesion rather than of the chemical properties of the modified base per se . It may be useful, therefore, to classify DNA base damage according to their effect on DNA conformation. The elucidation of the structures of the DNA lesions produced in situ in the living cell represents a prerequisite for the correlation of specific lesions with the biological effects and for the study of the cellular repair processes. Excision repair represents an ubiquitous mechanism in cells for the removal of damaged residues from the DNA. The most specific first step in excision repair is the recognition of the damage by an endonuclease followed by incision of the damaged DNA strand in the proximity of the damage. Several “repair endonucleases” have been characterized from bacteria while the search for the corresponding mammalian enzymes is only beginning. The second, probably less specific step, is the exonucleolytic degradation of the damaged portion of the DNA leading to the removal of the damaged residue. In E. coli the removal of both cyclobutane-type photodimers and γ-ray products of the 5,6-dihydroxy-dihydrothymine type is accomplished by the 5′→3′ exonuclease associated with polymerase I. All three E. coli polymerases appear to participate in the rebuilding of the degraded portion of the DNA. Studies on the corresponding enzymes in mammalian cells have been initiated. The last step of exicison repair involves the sealing of a phosphodiester bond of the DNA backbone and is accomplished by the enzyme polynucleotide ligase in bacterial and mammalian cells.