Nucleotide excision repair of chemically stabilized analogues of DNA interstrand cross-links produced from oxidized abasic sites.
Nucleotide excision repair of chemically stabilized analogues of DNA interstrand cross-links produced from oxidized abasic sites.
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DOI：
10.1021/bi500914d
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发表时间：
2014-09-23
期刊：
影响因子：
2.9
通讯作者：
Greenberg, Marc M.
中科院分区：
文献类型：
--
作者：
Ghosh, Souradyuti;Greenberg, Marc M.
核苷酸切除修复是细胞应对DNA链间交联（ICL）的主要途径。最近，发现从DNA骨架上提取氢原子后产生的C4′-氧化的（C4-AP）和C5′-氧化的脱碱基位点（DOB）可产生ICL。因为衍生自C4-AP和DOB的一些ICL太不稳定而不能在生物化学过程中表征，所以合成了化学稳定的类似物[Ghosh，S.，Greenberg，M. M.（2014）J. Org. Chem.79，5948-5957]。检查了含有衍生自C4-AP和DOB的ICL的稳定类似物的DNA底物的UVrABC切割。与C4′-氧化脱碱基位点相关的ICL的切口模式对于UvrABC底物是典型的。UvrABC切割含有C4-AP ICL类似物的底物的两条链，但它是一种较差的底物。UvrABC在8小时内切割<30%的C4-AP ICL类似物，提高了这种交联在细胞中被低效修复的可能性。此外，在切割含有C4-AP ICL类似物的内部标记的发夹底物时未检测到双链断裂。UvrABC更有效地切割DOB ICL的稳定类似物（在1小时内切割20%）。此外，切口图案是独特的，并且交联的底物被转化为单一产物，即双链断裂。模板链仅在交联dA的3′侧的模板链上切割。尽管UvrABC和这两种交联底物之间相互作用的结果彼此不同，但它们提供了看似简单的病变（C4-AP和DOB）如何对生化过程产生潜在的显著有害影响的额外例子。
Nucleotide excision repair is a primary pathway in cells for coping with DNA interstrand cross-links (ICLs). Recently, C4′-oxidized (C4-AP) and C5′-oxidized abasic sites (DOB) that are produced following hydrogen atom abstraction from the DNA backbone were found to produce ICLs. Because some of the ICLs derived from C4-AP and DOB are too unstable to characterize in biochemical processes, chemically stable analogues were synthesized [Ghosh, S., and Greenberg, M. M. (2014) J. Org. Chem.79, 5948–5957]. UvrABC incision of DNA substrates containing stabilized analogues of the ICLs derived from C4-AP and DOB was examined. The incision pattern for the ICL related to the C4′-oxidized abasic site was typical for UvrABC substrates. UvrABC cleaved both strands of the substrate containing the C4-AP ICL analogue, but it was a poor substrate. UvrABC incised <30% of the C4-AP ICL analogue over an 8 h period, raising the possibility that this cross-link will be inefficiently repaired in cells. Furthermore, double-strand breaks were not detected upon incision of an internally labeled hairpin substrate containing the C4-AP ICL analogue. UvrABC incised the stabilized analogue of the DOB ICL more efficiently (∼20% in 1 h). Furthermore, the incision pattern was unique, and the cross-linked substrate was converted into a single product, a double-strand break. The template strand was exclusively incised on the template strand on the 3′-side of the cross-linked dA. Although the outcomes of the interaction between UvrABC and these two cross-linked substrates are different from one another, they provide additional examples of how seemingly simple lesions (C4-AP and DOB) can potentially exert significant deleterious effects on biochemical processes.
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影响因子：
7.8
作者：
Greenberg, Marc M.
通讯作者：
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影响因子：
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影响因子：
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