DNA base excision repair: a mechanism of trinucleotide repeat expansion

Abstract

Expansion of trinucleotide repeat (TNR) sequences in human DNA is considered to be a key factor in the pathogenesis of more than 40 neurodegenerative diseases. TNR expansion occurs during DNA replication and also, as suggested by recent studies, during the repair of DNA lesions produced by oxidative stress. In particular, the oxidized guanine base, 8-oxoG, within sequences containing CAG repeats may induce formation of pro-expansion intermediates through strand slippage during DNA base excision repair (BER). In this article, we describe how oxidized DNA lesions are repaired by BER and discuss the importance of the coordinated activities of the key repair enzymes, such as DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase, in preventing strand slippage and TNR expansion.

Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair

“…In fact, the results from all studies have shown that TNR instability can be generated during any DNA metabolic pathways that involve formation of single-stranded DNA including replication (104,105), transcription (106), repair (11,12) and recombination (107).…”

“…In the human genome, typical non-B form structures arising from (CAG) n /(CTG) n , (CTG) n /(CAG) n , (CGG) n /(CCG) n and (GAA) n /(TTC) n sequence contexts include hairpins, tetraplexes and triplexes (85,86). These DNA secondary structures can cause DNA polymerase pausing and DNA slippage (108,109), replication fork stalling and collapse (86,97,98) Thus, inefficient BER leads to TNR expansion (11). A multi-nucleotide gap generated during BER could also allow the formation of a hairpin on the template strand that may mediate TNR deletion induced by DNA damages.…”

“…Pol β, a central component of BER, removes a native deoxyribose phosphate residue and fills in a single-nucleotide gap to fulfill the efficient single nucleotide BER (11). Pol β can also perform multi-nucleotide gap-filling synthesis and strand displacement synthesis that leads to the relatively inefficient long-patch BER (11).…”

“…Pol β can also perform multi-nucleotide gap-filling synthesis and strand displacement synthesis that leads to the relatively inefficient long-patch BER (11). Pol β multi-nucleotide gap-filling synthesis was found to promote CAG repeat expansion by producing extra repeat units (115), whereas its slippage synthesis is suggested to be involved in repeat deletion.…”

“…As a central component of BER, pol β fills in gaps, performs strand-displacement synthesis and modulates TNR stability during BER (11). Thus it may also play a critical role during BER in a hairpin loop.…”