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首页> 外文期刊>Journal of Molecular Biology >Repair of tandem base lesions in DNA by human cell extracts generates persisting single-strand breaks
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Repair of tandem base lesions in DNA by human cell extracts generates persisting single-strand breaks

机译：人类细胞提取物修复DNA中的串联碱基损伤产生持续的单链断裂

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Clustered DNA damage, where two or more lesions are located proximal to each other on the same or opposite DNA strands, is frequently produced as a result of exposure to ionising radiation. It has been suggested that such complex damaged sites pose problems for repair pathways. In this study, we addressed the question of how two 8-oxoguanine lesions, located two nucleotides apart on the same DNA strand, are repaired. We find that in human cell extracts repair of either of the 8-oxoguanine lesions within a tandem damaged site is initiated randomly and that the majority of the initiated repair proceeds to completion. However, a fraction of the initiated repair is delayed at the stage of an incised AP site and the rate of further processing of this incised AP site is dependent on the position of the remaining 8-oxoguanine. If the remaining 8-oxoguanine residue is located near the 5' terminus of the incised abasic site, repair continues as efficiently as repair of a single 8-oxoguanine residue. However, repair is delayed after the incision step when the remaining 8-oxoguanine residue is located near the 3' terminus. Although the presence of the 8-oxoguanine residue near the 3' terminus did not affect either DNA polymerase P activity or poly(ADP)ribose polymerase-1 affinity and turnover on an incised AP site, we find that 8-oxoguanine-DNA glycosylase has reduced ability to remove an 8-oxoguanine residue located near the 3' terminus of the incised AP site. We find that binding of the 8-oxoguanine-DNA glycosylase to this 8-oxoguanine residue inhibits DNA repair synthesis by DNA polymerase 0, thus delaying repair. We propose that interference between a DNA glycosylase and DNA polymerase during the repair of tandem lesions may lead to accumulation of the intermediate products that contain persisting DNA strand breaks. (c) 2005 Elsevier Ltd. All rights reserved.
机译：由于暴露于电离辐射，经常会产生簇状的DNA损伤，其中两个或多个损伤位于相同或相反的DNA链上彼此相邻。已经提出，这种复杂的受损部位为修复途径带来了问题。在这项研究中，我们解决了如何修复位于同一条DNA链上两个核苷酸分开的两个8-氧代鸟嘌呤损伤的问题。我们发现，在人类细胞提取物中，串联损伤位点内的8-氧代鸟嘌呤损伤之一的修复是随机启动的，并且大多数已启动的修复过程都已完成。但是，一部分开始的修复在切开的AP部位的阶段被延迟，并且对该切开的AP部位的进一步加工速率取决于剩余的8-氧鸟嘌呤的位置。如果剩余的8-氧鸟嘌呤残基位于切的无碱基位点的5'末端附近，则修复与单个8-氧鸟嘌呤残基的修复一样有效。但是，当剩余的8-氧代鸟嘌呤残基位于3'末端附近时，切开步骤后修复会延迟。尽管在3'末端附近存在8-氧鸟嘌呤残基不影响DNA聚合酶P活性或聚（ADP）核糖聚合酶-1亲和力和切开的AP位点的周转率，但我们发现8-氧鸟嘌呤-DNA糖基化酶具有降低了去除位于切开的AP位点3'末端附近的8-氧鸟嘌呤残基的能力。我们发现8-氧鸟嘌呤-DNA糖基化酶对此8-氧鸟嘌呤残基的结合抑制了DNA聚合酶0的DNA修复合成，从而延迟了修复。我们提出，在串联损伤修复期间，DNA糖基化酶和DNA聚合酶之间的干扰可能会导致包含持续DNA链断裂的中间产物的积累。 （c）2005 Elsevier Ltd.保留所有权利。

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