Base excision repair in physiology and pathology of the central nervous system

Abstract

Relatively low levels of antioxidant enzymes and high oxygen metabolism result in formation of numerous oxidized DNA lesions in the tissues of the central nervous system. Accumulation of damage in the DNA, due to continuous genotoxic stress, has been linked to both aging and the development of various neurodegenerative disorders. Different DNA repair pathways have evolved to successfully act on damaged DNA and prevent genomic instability. The predominant and essential DNA repair pathway for the removal of small DNA base lesions is base excision repair (BER). In this review we will discuss the current knowledge on the involvement of BER proteins in the maintenance of genetic stability in different brain regions and how changes in the levels of these proteins contribute to aging and the onset of neurodegenerative disorders.

Figure 1

Short-patch (SP-) and long-patch base excision repair (LP-BER) sub-pathways. The damaged base is recognized and excised by a DNA glycosylase, resulting often in AP site formation, which is further processed by APE1. Subsequent end-processing generates 3′-OH and 5′-phosphate (5′-P) termini, enabling access of repair Pols. Depending on the number of newly incorporated nucleotides, the BER pathway divides into two sub-pathways: short-patch BER (SP-BER) and long-patch BER (LP-BER). (A) In SP-BER, a Pol β-mediated single nucleotide incorporation is followed by strand ligation, catalyzed by the XRCC1/DNA ligase III complex; (B) In contrast, LP-BER synthesizes a repair patch consisting of 2–12 nucleotides by: (i) the Hit-and-Run mechanism involving alternating FEN1 cleavage and Pols β synthesis; or (ii) the strand-displacement DNA synthesis concerted by Pols β and δ/ɛ. The 5′-flap, created during strand-displacement DNA synthesis, is removed by the FEN1 generating a nick. The FEN1 created nick is sealed by DNA ligase I. For more details see text.