Coordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion
Coordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion
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DOI：
10.1074/jbc.m109.050286
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发表时间：
2009-10-09
影响因子：
4.8
通讯作者：
Wilson, Samuel H.
中科院分区：
文献类型：
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作者：
Liu, Yuan;Prasad, Rajendra;Wilson, Samuel H.
氧化DNA碱基8-氧鸟嘌呤（8-oxoG）与亨廷顿病相关的神经元CAG重复扩增有关，但目前尚不清楚这种DNA碱基损伤及其修复如何导致扩增。在这里，我们发现在野生型小鼠细胞提取物的8-oxoG修复过程中CAG重复序列的大小有限扩增。缺乏pol β和HMGB1的细胞提取物缺乏这种扩增。我们证明，在长补片碱基切除修复过程中，扩展是通过pol - β多核苷酸间隙填充DNA合成介导的。出乎意料的是，FEN1通过促进由链滑移形成的发夹的结扎来促进扩张。这种FEN1和聚合酶β (pol β)多核苷酸填补合成的交替作用是pol β和FEN1之间通常的配位解偶联的结果。HMGB1可能通过刺激APEI和FEN1分别形成单链断裂和可连接切口来促进扩张。这是第一次有报道表明，在长贴片BER过程中，pol β和FEN1协调的破坏会导致CAG重复扩增。
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 beta and HMGB1. We demonstrate that expansion is mediated through pol beta 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 beta (pol beta) multinucleotide gap-filling synthesis is the result of uncoupling of the usual coordination between pol beta and FEN1. HMGB1 probably promotes expansion by stimulating APEI and FEN1 in forming single strand breaks and ligatable nicks, respectively. This is the first report illustrating that disruption of pol beta and FEN1 coordination during long-patch BER results in CAG repeat expansion.