Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.
Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.
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DOI：
10.1002/ijc.27440
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发表时间：
2012-10-15
影响因子：
6.4
通讯作者：
Oh DH
中科院分区：
文献类型：
--
作者：
Demetriou SK;Ona-Vu K;Sullivan EM;Dong TK;Hsu SW;Oh DH
默克尔细胞多瘤病毒(MCV)感染促进默克尔细胞癌形成的途径对于了解这些癌症的发病机制具有重要意义。我们假设MCV T抗原抑制对紫外线辐射(UVR)诱导的DNA损伤的正常反应。MCV感染的细胞系(MKL-1)表现出紫外线过敏、DNA损伤修复受损和紫外线照射后细胞周期停滞，以及DNA损伤识别蛋白XPC水平下降。当在未感染的UISO细胞中异位表达时，突变型而不是野生型T抗原导致UVR诱导的环丁烷嘧啶二聚体修复丧失，XPC、p53和p21水平降低，而野生型和突变型T抗原均抑制UVR后细胞周期停滞。同样，只有正常成纤维细胞中的突变T抗原抑制DNA修复和XPC的表达，而突变和野生型T抗原都产生细胞周期失调。野生型T抗原表达产生大T、57kT和小T抗原，而突变型T抗原只能作为截短的大T抗原蛋白被检测到。野生型大T抗原而不是小T抗原的表达抑制了UISO细胞的G1检查点，但野生型大T和小T抗原都不影响DNA修复，这表明大T抗原会产生细胞周期缺陷，当突变时也可能损害DNA修复。这些结果表明，MCV表达T抗原可以抑制对UVR诱导的DNA损伤的关键反应，提示MCV介导的基因组稳定性的进行性丧失可能参与了Merkel细胞的癌变。
The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest following UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest following UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis.
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影响因子：
6.7
作者：
Laude HC;Jonchère B;Maubec E;Carlotti A;Marinho E;Couturaud B;Peter M;Sastre-Garau X;Avril MF;Dupin N;Rozenberg F
通讯作者：
Rozenberg F
DOI：
10.1083/jcb.125.3.625
发表时间：
1994-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lukas J;Müller H;Bartkova J;Spitkovsky D;Kjerulff AA;Jansen-Dürr P;Strauss M;Bartek J
通讯作者：
Bartek J
影响因子：
3.8
作者：
Lin, Patrick S.;McPherson, Lisa A.;Ford, James M.
通讯作者：
Ford, James M.
影响因子：
3.7
作者：
Mogha, Ariane;Fautrel, Alain;Galibert, Marie-Dominique
通讯作者：
Galibert, Marie-Dominique
影响因子：
168.9
作者：
Engels, EA;Frisch, M;Miller, RW
通讯作者：
Miller, RW