Genotoxic stress generates single- and double-strand DNA breaks either through direct damage by reactive oxygen species or as intermediates of DNA repair. Failure to detect and repair DNA strand breaks leads to deleterious consequences such as chromosomal aberrations, genomic instability and cell death. DNA strand breaks disrupt the superhelical state of cellular DNA, which further disturbs the chromatin architecture and gene activity regulation. Proteins from the poly(ADP-ribose) polymerase (PARP) family, such as PARP1 and PARP2, use NAD+ as a substrate to catalyse the synthesis of polymeric chains consisting of ADP-ribose units covalently attached to an acceptor molecule. PARP1 and PARP2 are regarded as DNA damage sensors that, upon activation by strand breaks, poly(ADP-ribosyl)ate themselves and nuclear acceptor proteins. Noteworthy, the regularly branched structure of poly(ADP-ribose) polymer suggests that the mechanism of its synthesis may involve circular movement of PARP1 around the DNA helix, with a branching point in PAR corresponding to one complete 360° turn. We propose that PARP1 stays bound to a DNA strand break end, but rotates around the helix displaced by the growing poly(ADP-ribose) chain, and that this rotation could introduce positive supercoils into damaged chromosomal DNA. This topology modulation would enable nucleosome displacement and chromatin decondensation around the lesion site, facilitating the access of DNA repair proteins or transcription factors. PARP1-mediated DNA supercoiling can be transmitted over long distances, resulting in changes in the high-order chromatin structures. The available structures of PARP1 are consistent with the strand break-induced PAR synthesis as a driving force for PARP1 rotation around the DNA axis.

中文翻译：

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深入了解聚（ADP-核糖基）在DNA拓扑调控和对DNA损伤的响应中的作用。

基因毒性应激通过活性氧的直接破坏或作为DNA修复的中间体而产生单链和双链DNA断裂。无法检测和修复DNA链断裂会导致有害后果，例如染色体畸变，基因组不稳定和细胞死亡。DNA链断裂会破坏细胞DNA的超螺旋状态，从而进一步干扰染色质结构和基因活性调节。聚（ADP-核糖）聚合酶（PARP）家族的蛋白质（例如PARP1和PARP2）使用NAD +作为底物来催化由共价连接至受体分子的ADP-核糖单元组成的聚合物链的合成。PARP1和PARP2被认为是DNA损伤传感器，通过链断裂激活后，聚（ADP-核糖基）自身和核受体蛋白就会被破坏。值得注意的是 聚（ADP-核糖）聚合物的规则分支结构表明，其合成机理可能涉及PARP1围绕DNA螺旋的圆周运动，PAR中的分支点对应于一个完整的360°转角。我们建议PARP1保持绑定到DNA链断裂末端，但围绕由增长的聚（ADP-核糖）链取代的螺旋旋转，并且这种旋转可能将正超螺旋引入受损的染色体DNA。这种拓扑调节将使核小体移位和染色质在病灶部位附近缩聚，促进DNA修复蛋白或转录因子的进入。PARP1介导的DNA超螺旋可以长距离传播，从而导致高级染色质结构发生变化。