Base Excision Repair

A. Base excision repair by glycosylases and apyrimidmic or apurinic endonucleases

Bases modified by deamination can be repaired by a group of enzymes called DNA glycosylases, which specifically hydrolyze the N-glycosyl bond of that base and the deoxyribose of the DNA backbone generating an apyrimidinic or an apurinic site (AP site) (Fig. 27.7). These are small, highly specific enzymes that require no cofactor for functioning. They are the most highly conserved proteins, attesting to the evolutionary unity both structurally and mechanistically from bacteria to man. As a consequence of DNA glycosylase action, the AP sites generated in the DNA are acted on by a phosphodiesterase (Fig. 27.8) specific for such sites that can nick the DNA 5' and/or 3' to such damaged sites. If there is a sequential action of a 5' acting and a 3' acting AP endonuclease, the AP site is excised generating a gap in the DNA strand.

FIGURE 27.7 DNA glycosylases hydrolyze the N-glycosyl bond between damaged bases and deoxyribose generating an AP (apyrimidinic or apurinic) site (arrow).
FIGURE 27.8 Endonucleases recognize AP sites and hydrolyze the phosphodiester bonds 3', 5', or both sides of the deoxyribose moiety in damaged DNA.

B. Glycosylase-associated AP endonucleases

An enzyme from bacteria and phage-infected bacteria, encoded in the latter case by a single gene (den), hydrolyzes the N-glycosyl bond of the 5' thymine moiety of a pyrimidine dimer followed by hydrolysis of the phosphodiester bond between the two thymine residues of the dimer (Fig. 27.9). This enzyme, referred to as the pyrimidine dimer DNA glycosylase, is found in Micrococcus luteus and phage T4-infected E. coli. This small, uncomplicated enzyme does not require cofactors and is presumed to act by a series of linked 3 elimination reactions. An enzyme behaving in a similar glycosylase-endonuclease fashion but acting on the radiolysis product of thymine is thymine glycol, which has been isolated from E. coli and is referred to as endonuclease III.

FIGURE 27.9 The same enzyme that can hydrolyze the N-glycosyl residue of a damaged nucleotide also hydrolyzes the phosphodiester bond linking the AP site generated in the first N-glycosylase reaction.

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