Nucleotide Excision Repair (NER) is an important DNA excision repair system in cells. It is able to repair and replace damaged regions up to 30 bases in length and it is directed by the undamaged template strand. Common DNA damages are occurred due to ultraviolet radiation and NER protects DNA by repairing those damages immediately prior to becoming mutations and passing into future generations or cause diseases. NER specifically provides protection against mutations caused indirectly by exogenous factors such as environmental and chemical carcinogens. NER is seen in almost all organisms, and it recognizes damages which cause significant distortion in the DNA helix.

The NER process involves the action of many proteins such as  XPA, XPB, XPC, XPD, XPE, XPF, XPG, CSA, CSB, etc. and proceeds via several cut and paste-like mechanisms. Those proteins are essential for the completion of the repair process, and a defect in one of the NER proteins is vital and can cause rare recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive form of the brittle hair disorder trichothiodystrophy (TTD).

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紫外线引起的DNA损伤修复的主要路径,主要方式两种,分别叫做global genome NER (GG‑NER) 和 transcription-coupled NER (TC‑NER)。

一般紫外线引起的DNA损伤可以使胸腺嘧啶发生[2+2]光化学反应产生四元环二聚体或者6-4加合物,一系列NER修复蛋白识别并且聚集到损伤部位,切断损伤部位附近的一小段核苷酸序列,然后切断部位再在DNA聚合酶以及连接酶作用下把gap给补充起来得到正常双链,图解如下

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如,UvrABC系统修复T-T dimer导致的结构变形(uvr: Ultraviolet repair )

切除修复过程中,损伤的DNA链由切除酶(excinuclease)切除,此酶也是一种核酸内切酶。编码内切酶是由多个亚基组成的Uvr基因。在E畅coli中,Uvr ABC 切除酶包括3种亚基,UvrA,UvrB和UvrC。

大肠杆菌中的UvrA可识别DNA损伤部位,引导UvrB和UvrC 与其结合形成复合体。由UvrC 完成对DNA 单链的切割,12个碱基的DNA链由解链酶Ⅱ作用脱离,然后由DNA聚合酶Ⅲ以互补链合成DNA,DNA连接酶封闭其缺口,从而完成DNA损伤修复


由于碱基的不稳定所造成的的碱基化学损伤,以及辐射引发的胸腺嘧啶二聚体,可以经过核苷酸切除修复系统而修复(大肠杆菌中是Uvr修复)。另外非复制期的碱基化学损伤,还有糖基化酶修复系统,这是一种碱基切除修复。

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DNA糖基化酶(DNA glycosylases)识别并切除损伤部位的碱基,得到无碱基位点(Abasic Site),再被脱嘌呤嘧啶内切酶(Apurinic/apyrimidinic endonuclease, APE)切除,引起单链断裂(single strand break),断裂部位的5'端存在一个磷酸脱氧核糖(Deoxyribose5-phosphate, dRP),该部位被DNA聚合酶β (DNA polymerase β, Polβ)切除,然后Polβ再引入一个正常的核苷酸,最后通过Lig III-XRCC1复合物将其连接得到正常的双链。以上是Short-patch BER,另外通过NEIL1-3 DNA糖基化酶以及Long-patch BER修复路径不详说了,下图很清楚

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