Testing excision models for responses of mismatch-repair systems to UV photoproducts in DNA.
Testing excision models for responses of mismatch-repair systems to UV photoproducts in DNA.
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测试切除模型以了解错配修复系统对 DNA 中紫外光产物的反应。
DOI：
10.1002/em.20206
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发表时间：
2006
期刊：
影响因子：
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通讯作者：
Hays,JohnB
中科院分区：
文献类型：
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作者：
Wang,Huxian;Hoffman,PeterD;Lawrence,Christopher;Hays,JohnB
错配修复（MMR）系统纠正DNA复制错误，并对各种DNA损伤做出反应。先前的观察表明，MMR拮抗UV诱变，并且错配识别蛋白异源二聚体MSH 2·MSH 6（MutSα）选择性地结合含有“错配”光产物（T[CPD]T/AG，T[6 - 4]T/AG）但不含“匹配”光产物（T[CPD]T/AA，T[6 - 4]T/AA）的DNA，这表明错配光产物会引起类似于错配碱基的MMR切除。然后，切除插入相对于模板光产物的不正确核苷酸可能会阻止UV诱导的突变。我们测试了T[CPD]T/AGDNA，在一个序列背景下，它基本上是由hMutSα结合，并在其他三个背景下，刺激3′ MMR切除哺乳动物核提取物。T[CPD]T/AG在HeLa提取物或缺乏光产物结合蛋白DDB或XPC·hHR 23 B的提取物中无活性，这与核苷酸切除修复途径的干扰有关。相对于同源双链体对照，先前与hMutSα和MLH 2·PMS 2（hMutLα）孵育未增加切除。T[6 - 4]T/AG也不能引起切除，T/G、C/A和T/T底物，即使与hMutSα的结合不如T[CPD]T/AG底物，也能有效地引起切除。即使是含有三个T[CPD]T/AG photoproducts（在不同的情况下）的基板没有显着挑起切除。因此，MMR可能通过非切除机制抑制UV诱变。Environ.摩尔诱变剂，2006.© 2006 Wiley利斯公司
Mismatch‐repair (MMR) systems correct DNA replication errors and respond to a variety of DNA lesions. Previous observations that MMR antagonizes UV mutagenesis, and that the mismatch‐recognition protein heterodimer MSH2•MSH6 (MutSα) selectively binds DNA containing “mismatched” photoproducts (T[CPD]T/AG, T[6‐4]T/AG) but not “matched” photoproducts (T[CPD]T/AA, T[6‐4]T/AA), suggested that mismatched photoproducts would provoke MMR excision similar to mismatched bases. Excision of incorrect nucleotides inserted opposite template photoproducts might then prevent UV‐induced mutation. We tested T[CPD]T/AGDNA, in a sequence context in which it is bound substantially by hMutSα and in three other contexts, for stimulation of 3′ MMR excision in mammalian nuclear extracts. T[CPD]T/AGwas inactive in HeLa extracts, or in extracts deficient in the photoproduct‐binding proteins DDB or XPC• hHR23B, arguing against interference from the nucleotide excision repair pathway. Prior incubation with hMutSα and MLH2·PMS2 (hMutLα) did not increase excision relative to homoduplex controls. T[6‐4]T/AGalso failed to provoke excision.T/G,C/A, andT/Tsubstrates, even though bound by hMutSα no better than T[CPD]T/AGsubstrates, efficiently provoked excision. Even a substrate containing three T[CPD]T/AGphotoproducts (in different contexts) did not significantly provoke excision. Thus, MMR may suppress UV mutagenesis by non‐excisive mechanisms. Environ. Mol. Mutagen., 2006. © 2006 Wiley‐Liss, Inc.