DNA base excision repair

Introduction

Cellular genomes suffer extensive damage via hydrolysis, oxidation & alkylation of DNA. The repair system primarily involved in repair of this damage is the base excision repair pathway. Key enzymes in this pathway are DNA glycosylases, which remove different types of modified or damaged bases by cleavage of the N-glycosidic bond between the base & the deoxyribose moieties of the nucleotide residues. Different DNA glycosylases remove different kinds of damage, & the specificity of the repair pathway is determined by the type of glycosylase involved. Once the base is removed, the apurinic/apyrimidinic (AP)-site is removed by an AP-endonuclease or an AP-lyase, which cleave the DNA strand 5' or 3' to the AP-site, respectively. The remaining deoxyribose phosphate residue is excised by a phosphodiesterase; the resulting gap is filled by DNA polymerase-beta, & the strand sealed by DNA ligase.

* see figure

The most frequent type of endogenous DNA damage is probably the AP-site. These arise spontaneously by hydrolytic loss of purine bases at a frequency approaching 10,000/human cell/day. Another frequent hydrolysis reaction is the deamination of cytosine to uracil & (at a much lower frequency) adenine to hypoxanthine. Because the deaminated base derivatives have altered coding properties, these will produce mutations unless they are removed.

In addition to spontaneous decay by hydrolysis, endogenous DNA damage is also formed by oxidation & alkylation. S-adenosylmethionine (SAM) will methylate adenine to form 3-methyladenine at a rate of several hundred/human cell/day. 8-hydroxyguanine & thymine glycol are products of oxidative DNA damage.

Apparently mitochondria have capacity for base excision repair.

More general terms

• DNA repair