Nucleotide deficiency promotes genomic instability in early stages of cancer development.
Nucleotide deficiency promotes genomic instability in early stages of cancer development.
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DOI：
10.1016/j.cell.2011.03.044
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发表时间：
2011-04-29
期刊：
影响因子：
64.5
通讯作者：
Kerem B
中科院分区：
文献类型：
--
作者：
Bester AC;Roniger M;Oren YS;Im MM;Sarni D;Chaoat M;Bensimon A;Zamir G;Shewach DS;Kerem B
早期癌症阶段的染色体不稳定是由DNA复制的压力引起的。在这种情况下，复制扰动的分子基础目前尚不清楚。我们研究了S期进入和细胞增殖的调节因子Rb-E2F通路异常激活时细胞的复制动力学。HPV-16 E6/E7或细胞周期蛋白E癌基因对该途径的异常激活显著降低了新转化细胞中的细胞核苷酸水平。外源提供的核苷挽救了复制应激和DNA损伤，并显著降低了癌基因诱导的转化。通过表达转录因子c-myc介导的核苷酸生物合成基因转录增加，增加了核苷酸库，也挽救了复制诱导的DNA损伤。我们的研究结果提出了一个早期肿瘤发生的模型，其中调节细胞增殖的因子的不协调激活导致核苷酸不足，无法支持正常复制和基因组稳定性。
Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
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通讯作者：
di Fagagna, Fabrizio d'Adda
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作者：
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通讯作者：
Dang CV
影响因子：
16
作者：
Coquelle, A;Toledo, F;Debatisse, M
通讯作者：
Debatisse, M
影响因子：
10.5
作者：
Ge, Xin Quan;Jackson, Dean A;Blow, J Julian
通讯作者：
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