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首页> 外文期刊>Biochemistry >HMGB1 Stimulates Activity of Polymerase beta on Nucleosome Substrates
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HMGB1 Stimulates Activity of Polymerase beta on Nucleosome Substrates

机译：HMGB1 刺激核小体底物上聚合酶 β 的活性

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摘要

The process of base excision repair (BER) recognizes and repairs small lesions or inappropriate bases on DNA through either a short-patch or long-patch pathway. The enzymes involved in BER have been well-characterized on DNA substrates, and, somewhat surprisingly, many of these enzymes, including several DNA glycosylases, AP endonuclease (APE), FEN1 endonuclease, and DNA ligases, have been shown to have activity on DNA substrates within nucleosomes. DNA polymerase beta (Pol beta), however, exhibits drastically reduced or no activity on nucleosomal DNA. Interestingly, acetylation of Pol beta, by the acetyltransferase p300, inhibits its 5' dRP-lyase activity and presumably pushes repair of DNA substrates through the long-patch base excision repair (LP-BER) pathway. In addition to the major enzymes involved in BER, a chromatin architectural factor, HMGB1, was found to directly interact with and enhance the activity of APE1 and FEN1, and thus may aid in altering the structure of the nucleosome to be more accessible to BER factors. In this work, we investigated whether acetylation of Pol beta, either alone or in conjunction with HMGB1, facilitates its activity on nucleosome substrates. We find acetylated Pol beta exhibits enhanced strand displacement synthesis activity on DNA substrates, but, similar to the unmodified enzyme, has little or no activity on nucleosomes. Preincubation of DNA templates with HMGB1 has little or no stimulatory effect on Pol beta and even is inhibitory at higher concentrations. In contrast, preincubation of nucleosomes with HMGB1 rescues Pol beta gap-filling activity in nucleosomes, suggesting that this factor may help overcome the repressive effects of chromatin.
机译：碱基切除修复 （BER） 过程通过短贴片或长贴片途径识别和修复 DNA 上的小病变或不适当的碱基。参与BER的酶已经在DNA底物上得到了很好的表征，令人惊讶的是，其中许多酶，包括几种DNA糖基化酶、AP核酸内切酶（APE）、FEN1核酸内切酶和DNA连接酶，已被证明对核小体内的DNA底物具有活性。然而，DNA 聚合酶 β （Pol beta） 在核小体 DNA 上表现出急剧降低或没有活性。有趣的是，乙酰转移酶 p300 对 Pol β 的乙酰化抑制了其 5' dRP-裂解酶活性，并可能通过长贴片碱基切除修复 （LP-BER） 途径推动 DNA 底物的修复。除了参与BER的主要酶外，还发现染色质结构因子HMGB1直接与APE1和FEN1相互作用并增强其活性，因此可能有助于改变核小体的结构，使其更容易被BER因子所接近。在这项工作中，我们研究了 Pol β 的乙酰化，无论是单独还是与 HMGB1 联合，是否促进其在核小体底物上的活性。我们发现乙酰化的 Pol β 在 DNA 底物上表现出增强的链置换合成活性，但与未修饰的酶类似，在核小体上几乎没有活性。用 HMGB1 预孵育 DNA 模板对 Pol β 几乎没有刺激作用，甚至在较高浓度下具有抑制作用。相比之下，用 HMGB1 预孵育核小体可挽救核小体中 Pol β 间隙填充活性，这表明该因子可能有助于克服染色质的抑制作用。

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