PostExcision Events in Human Nucleotide Excision Repair.
PostExcision Events in Human Nucleotide Excision Repair.
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DOI：
10.1111/php.12641
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发表时间：
2017-01
影响因子：
3.3
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Kemp MG;Hu J
核苷酸切除修复系统从人类基因组中移除各种DNA损伤，包括由紫外线(UV)波长的阳光诱导的光产物。核苷酸切除修复的一个明显特征是它的双重切割机制，在损伤的DNA链上发生两次核溶解切割事件，在病变周围的位置产生含有损伤的DNA寡核苷酸和大约30个核苷酸的单链DNA缺口。尽管核苷酸切除修复的早期事件，包括病变识别和双重切开，已经被详细地探索和合理地理解，但单链缺口和切除的修复寡核苷酸产物的命运还没有被广泛地研究。在这篇综述中，讨论了核苷酸切除修复的这些鲜为人知的方面的最新发现，并支持这样的概念，即切开后缝隙和切除的寡核苷酸处理是细胞对紫外线和其他环境致癌物诱导的DNA损伤反应的关键步骤。这些修复后期的缺陷会导致细胞死亡和其他DNA损伤信号反应，因此可能会导致与暴露在紫外线波长的阳光下相关的许多人类疾病状态，包括皮肤癌、衰老和自身免疫。人类核苷酸切除修复示意图。紫外线诱导DNA中紫外光产物的形成，包括图中所示的具有代表性的胸腺嘧啶二聚体。紫外光产物的~20±5个磷酸二酯键5‘和6±3个核苷酸磷酸二酯键3’发生两次核裂解切割，生成一个~30个核苷酸长的缺口DNA双链和一个30个核苷酸长的含损伤的DNA寡核苷酸。DNA修复反应的完成需要DNA修复合成和连接，以填补被切除的、含有损伤的DNA寡核苷酸的缺口和降解。
The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, including photoproducts induced by ultraviolet (UV) wavelengths of sunlight. A defining feature of nucleotide excision repair is its dual incision mechanism, in which two nucleolytic incision events on the damaged strand of DNA at sites bracketing the lesion generate a damage-containing DNA oligonucleotide and a single-stranded DNA gap approximately 30 nucleotides in length. Although the early events of nucleotide excision repair, which include lesion recognition and the dual incisions, have been explored in detail and are reasonably well understood, the fate of the single-stranded gaps and excised oligonucleotide products of repair have not been as extensively examined. In this review, recent findings that address these less-explored aspects of nucleotide excision repair are discussed and support the concept that post-incision gap and excised oligonucleotide processing are critical steps in the cellular response to DNA damage induced by UV light and other environmental carcinogens. Defects in these latter stages of repair lead to cell death and other DNA damage signaling responses and may therefore contribute to a number of human disease states associated with exposure to UV wavelengths of sunlight, including skin cancer, aging, and autoimmunity. Schematic of human nucleotide excision repair. UV induces the formation of UV photoproducts in DNA, including a representative thymine dimer indicated in the figure. Two nucleolytic incision events take place ~20 ± 5 phosphodiester bonds 5’ and 6 ± 3 nt phosphodiester bonds 3’ of the UV photoproduct to generate an ~30-nt-long gapped DNA duplex and an 30-nt-long damage-containing DNA oligonucleotide. Completion of the DNA repair reaction requires DNA repair synthesis and ligation to fill in the gap and degradation of the excised, damage-containing DNA oligonucleotide.