Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability.
Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability.
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DOI：
10.1093/nar/gkv222
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发表时间：
2015-04-20
影响因子：
14.9
通讯作者：
Dianov GL
中科院分区：
文献类型：
--
作者：
Markkanen E;Fischer R;Ledentcova M;Kessler BM;Dianov GL
由外源性诱变引起的遗传不稳定与癌症的发生密切相关。然而，即使在没有压力的细胞中，DNA也会因其固有的化学不稳定性和细胞内环境而发生大量的自发改变。碱基切除修复（BER）是负责修复这些病变的主要细胞途径，由于BER活性缺乏会导致DNA损伤，因此有人提出它可能引发散发性癌症的发展。然而，这个模型的实验证据仍然不一致和难以捉摸。在这里，我们使用细胞培养中氨基酸的稳定同位素标记（SILAC）对BER缺乏的人类细胞进行了蛋白质组学分析，并证明BER缺乏引起遗传不稳定性，导致基因表达的剧烈变化，类似于许多癌症中发现的变化。我们观察到组织稳态、丝氨酸生物合成、单碳和氨基酸代谢的深刻变化，所有这些都被确定为癌细胞的“标志”。本研究首次描述了内源性DNA损伤修复缺陷细胞的基因表达变化特征。这些表达变化类似于在癌细胞中观察到的，表明遗传不稳定的BER缺陷细胞可能是癌前细胞的来源。
Genetic instability, provoked by exogenous mutagens, is well linked to initiation of cancer. However, even in unstressed cells, DNA undergoes a plethora of spontaneous alterations provoked by its inherent chemical instability and the intracellular milieu. Base excision repair (BER) is the major cellular pathway responsible for repair of these lesions, and as deficiency in BER activity results in DNA damage it has been proposed that it may trigger the development of sporadic cancers. Nevertheless, experimental evidence for this model remains inconsistent and elusive. Here, we performed a proteomic analysis of BER deficient human cells using stable isotope labelling with amino acids in cell culture (SILAC), and demonstrate that BER deficiency, which induces genetic instability, results in dramatic changes in gene expression, resembling changes found in many cancers. We observed profound alterations in tissue homeostasis, serine biosynthesis, and one-carbon- and amino acid metabolism, all of which have been identified as cancer cell ‘hallmarks’. For the first time, this study describes gene expression changes characteristic for cells deficient in repair of endogenous DNA lesions by BER. These expression changes resemble those observed in cancer cells, suggesting that genetically unstable BER deficient cells may be a source of pre-cancerous cells.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
14.8
作者：
Olive, Peggy L.;Banath, Judit P.
通讯作者：
Banath, Judit P.
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
14.9
作者：
Dianov GL;Hübscher U
通讯作者：
Hübscher U
影响因子：
5.6
作者：
Bosshard M;Markkanen E;van Loon B
通讯作者：
van Loon B