Coordination between polymerase β and FEN1 can modulate CAG repeat expansion
Article
Liu, Y, Prasad, R, Beard, WA et al. (2009). Coordination between polymerase β and FEN1 can modulate CAG repeat expansion
. JOURNAL OF BIOLOGICAL CHEMISTRY, 284(41), 28352-28366. 10.1074/jbc.M109.050286
Liu, Y, Prasad, R, Beard, WA et al. (2009). Coordination between polymerase β and FEN1 can modulate CAG repeat expansion
. JOURNAL OF BIOLOGICAL CHEMISTRY, 284(41), 28352-28366. 10.1074/jbc.M109.050286
The oxidized DNA base 8-oxoguanine (8-oxoG) is implicated in neuronal CAG repeat expansion associated with Huntington disease, yet it is unclear how such a DNA base lesion and its repair might cause the expansion. Here, we discovered size-limited expansion of CAG repeats during repair of 8-oxoG in a wildtype mouse cell extract. This expansion was deficient in extracts from cells lacking pol β and HMGB1. We demonstrate that expansion is mediated through pol β multinucleotide gap-filling DNA synthesis during long-patch base excision repair. Unexpectedly, FEN1 promotes expansion by facilitating ligation of hairpins formed by strand slippage. This alternate role of FEN1 and the polymerase β (pol β) multinucleotide gap-filling synthesis is the result of uncoupling of the usual coordination between pol β and FEN1. HMGB1 probably promotes expansion by stimulating APE1 and FEN1 in forming single strand breaks and ligatable nicks, respectively. This is the first report illustrating that disruption of pol β and FEN1 coordination during long-patch BER results in CAG repeat expansion.
