Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest.
Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest.
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DOI：
10.1186/1471-2407-5-135
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发表时间：
2005-10-19
期刊：
影响因子：
3.8
通讯作者：
Owen LB
中科院分区：
文献类型：
--
作者：
Lo HL;Nakajima S;Ma L;Walter B;Yasui A;Ethell DW;Owen LB
紫外线诱导的损伤可诱导细胞凋亡或触发DNA修复机制。人们认为，轻微的DNA损伤会使细胞周期停止，从而进行有效的修复，而更严重的损伤会导致细胞凋亡。在两种主要类型的紫外线诱导的DNA损伤中，有报道称CPD的修复而不是6-4PP的修复可以消除突变。为了研究两种主要形式的紫外线诱导的DNA损伤是否能诱导不同的生物学效应，我们将含有CPD光解酶或6-4 PP光解酶的ner缺陷细胞暴露在紫外线下，观察细胞周期和凋亡的变化。此外，在体外和体内测试了CPD的分子模拟物pTpT诱导细胞死亡和细胞周期改变的能力。用CPD-光解酶或6-4PP光解酶稳定转染ner缺陷XPA细胞，特异性修复CPD或6-4PP。在300 J/m2的UVB照射下，提供光活化光（PR， 60 kJ/m2的UVA）用于光解酶的激活和DNA修复。24h后流式细胞术检测DNA含量，亚g1染色显示凋亡细胞。为了证实对CPD病变的影响，我们还在体外和体内测试了CPD的分子模拟物pTpT对细胞周期和凋亡的影响。UVB暴露后6-4PP损伤的特异性修复导致细胞凋亡的显著减少。这些结果表明，6-4PP病变可能是uvb诱导细胞凋亡的主要诱因。CPD损伤的修复（尽管它们在紫外线损伤的细胞中相对丰富）对诱导细胞凋亡的影响很小。CPD的分子模拟物（二核苷酸pTpT）可以模拟UVB对细胞周期阻滞的作用，但对诱导细胞凋亡无效。细胞对紫外线诱导的6-4PP病变的主要反应是触发凋亡程序，而细胞对CPD病变的反应似乎主要涉及细胞周期阻滞。这些结果提示CPD和6-4 PP可能在紫外线损伤细胞中诱导不同的生物学效应。
UV-induced damage can induce apoptosis or trigger DNA repair mechanisms. Minor DNA damage is thought to halt the cell cycle to allow effective repair, while more severe damage can induce an apoptotic program. Of the two major types of UV-induced DNA lesions, it has been reported that repair of CPD, but not 6-4PP, abrogates mutation. To address whether the two major forms of UV-induced DNA damage, can induce differential biological effects, NER-deficient cells containing either CPD photolyase or 6-4 PP photolyase were exposed to UV and examined for alterations in cell cycle and apoptosis. In addition, pTpT, a molecular mimic of CPD was tested in vitro and in vivo for the ability to induce cell death and cell cycle alterations. NER-deficient XPA cells were stably transfected with CPD-photolyase or 6-4PP photolyase to specifically repair only CPD or only 6-4PP. After 300 J/m2 UVB exposure photoreactivation light (PR, UVA 60 kJ/m2) was provided for photolyase activation and DNA repair. Apoptosis was monitored 24 hours later by flow cytometric analysis of DNA content, using sub-G1 staining to indicate apoptotic cells. To confirm the effects observed with CPD lesions, the molecular mimic of CPD, pTpT, was also tested in vitro and in vivo for its effect on cell cycle and apoptosis. The specific repair of 6-4PP lesions after UVB exposure resulted in a dramatic reduction in apoptosis. These findings suggested that 6-4PP lesions may be the primary inducer of UVB-induced apoptosis. Repair of CPD lesions (despite their relative abundance in the UV-damaged cell) had little effect on the induction of apoptosis. Supporting these findings, the molecular mimic of CPD, (dinucleotide pTpT) could mimic the effects of UVB on cell cycle arrest, but were ineffective to induce apoptosis. The primary response of the cell to UV-induced 6-4PP lesions is to trigger an apoptotic program whereas the response of the cell to CPD lesions appears to principally involve cell cycle arrest. These findings suggest that CPD and 6-4 PP may induce differential biological effects in the UV-damaged cell.
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影响因子：
56.9
作者：
Hill, LL;Ouhtit, A;Owen-Schaub, LB
通讯作者：
Owen-Schaub, LB
影响因子：
6.5
作者：
Mitchell, DL;Byrom, M;Lowery, MG
通讯作者：
Lowery, MG
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1073/pnas.78.6.3388
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
LIPPKE, JA;GORDON, LK;HASELTINE, WA
通讯作者：
HASELTINE, WA
影响因子：
6
作者：
Ouhtit, A;Gorny, A;Ananthaswamy, HN
通讯作者：
Ananthaswamy, HN