DNA Damage Laboratory of Food Science Department, Faculty of Pharmacy, Medical University of Lodz, ul. Muszynskiego 1, 90-151 Lodz, Poland.
Molecules. 2021 Nov 22;26(22):7042. doi: 10.3390/molecules26227042.
The 5',8-cyclo-2'-deoxypurines (cdPus) affect the DNA structure. When these bulky structures are a part of clustered DNA lesions (CDL), they affect the repair of the other lesions within the cluster. Mitochondria are crucial for cell survival and have their own genome, hence, are highly interesting in the context of CDL repair. However, no studies are exploring this topic. Here, the initial stages of mitochondrial base excision repair (mtBER) were considered-the strand incision and elongation. The repair of a single lesion (apurinic site (AP site)) accompanying the cdPu within the double-stranded CDL has been investigated for the first time. The type of cdPu, its diastereomeric form, and the interlesion distance were taken into consideration. For these studies, the established experimental model of short oligonucleotides (containing AP sites located ≤7 base pairs to the cdPu in both directions) and mitochondrial extracts of the xrs5 cells were used. The obtained results have shown that the presence of cdPus influenced the processing of an AP site within the CDL. Levels of strand incision and elongation were higher for oligos containing RcdA and ScdG than for those with ScdA and RcdG. Investigated stages of mtBER were more efficient for DNA containing AP sites located on 5'-end side of cdPu than on its 3'-end side. In conclusion, the presence of cdPus in mtDNA structure may affect mtBER (processing the second mutagenic lesion within the CDL). As impaired repair processes may lead to serious biological consequences, further studies concerning the mitochondrial repair of CDL are highly demanded.
5',8-环-2'-脱氧嘌呤（cdPus）会影响 DNA 结构。当这些大块结构成为簇状 DNA 损伤（CDL）的一部分时，它们会影响簇内其他损伤的修复。线粒体对于细胞存活至关重要，并且拥有自己的基因组，因此在 CDL 修复方面非常有趣。然而，目前尚无研究探索这一课题。在这里，我们考虑了线粒体碱基切除修复（mtBER）的初始阶段——链切割和延伸。首次研究了在双链 CDL 中伴随 cdPu 的单个损伤（无嘌呤/嘧啶位点（AP 位点））的修复。考虑了 cdPu 的类型、其非对映异构体形式和损伤间距离。为此，我们使用了已建立的短寡核苷酸实验模型（包含 AP 位点，其在双链体中距 cdPu 的两个方向上均≤7 个碱基）和 xrs5 细胞的线粒体提取物。研究结果表明，cdPus 的存在会影响 CDL 中 AP 位点的处理。含有 RcdA 和 ScdG 的寡核苷酸的链切割和延伸水平高于含有 ScdA 和 RcdG 的寡核苷酸。对于位于 cdPu 5'端的 DNA，所研究的 mtBER 阶段比位于 3'端的效率更高。总之，cdPus 在 mtDNA 结构中的存在可能会影响 mtBER（处理 CDL 内的第二个诱变损伤）。由于受损的修复过程可能会导致严重的生物学后果，因此非常需要进一步研究 CDL 的线粒体修复。
