High-mobility group A1 proteins inhibit expression of nucleotide excision repair factor xeroderma pigmentosum group A
High-mobility group A1 proteins inhibit expression of nucleotide excision repair factor xeroderma pigmentosum group A
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DOI：
10.1158/0008-5472.can-06-1689
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Reeves, Raymond
中科院分区：
文献类型：
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作者：
Adair, Jennifer E.;Maloney, Scott C.;Reeves, Raymond
过表达高迁移率族A1（HMGA 1）蛋白的细胞在暴露于DNA损伤剂后表现出核苷酸切除修复（NER）缺陷，这种情况可以通过人为降低这些非组蛋白的细胞内水平来改善。这种NER抑制的一种可能机制是下调NER中涉及的蛋白质，例如着色性干皮病互补组A（XPA）。微阵列和逆转录-PCR数据表明，与非HMGA 1表达细胞相比，在过表达HMGA 1蛋白的转基因MCF-7细胞中，细胞内XPA mRNA降低2.6倍。XPA蛋白水平在表达HMGA 1的MCF-7细胞中也类似于低3倍。此外，尽管在UV暴露后30分钟在正常MCF-7细胞中观察到XPA蛋白的> 2倍诱导，但在表达HMGA 1的MCF-7细胞中没有观察到XPA蛋白的明显诱导。从机制上讲，我们提出了染色质免疫沉淀和启动子位点特异性诱变证据，通过结合内源性XPA基因启动子中的负调控元件，将HMGA 1与XPA转录的抑制联系起来。在表型上，表达HMGA 1的细胞表现出环丁烷嘧啶二聚体损伤的受损清除，这是表达低水平XPA的细胞的特征。重要的是，我们表明，恢复表达野生型XPA的HMGA 1表达细胞拯救LTV抗性与正常MCF-7细胞。总之，这些数据提供了强有力的实验证据，证明HMGA 1蛋白是。参与抑制XPA表达，导致过表达这些蛋白质的细胞中UV敏感性增加。由于HMGA 1蛋白在大多数自然发生的癌症中过表达，细胞浓度的增加与转移潜力的增加和患者预后不良相关，因此目前的研究结果为以前未知的肿瘤进展机制提供了新的见解。
Cells that overexpress high-mobility group A1 (HMGA1) proteins exhibit deficient nucleotide excision repair (NER) after exposure to DNA-damaging agents, a condition ameliorated by artificially lowering intracellular levels of these nonhistone proteins. One possible mechanism for this NER inhibition is down-regulation of proteins involved in NER, such as xeroderma pigmentosum complimentation group A (XPA). Microarray and reverse transcription-PCR data indicate a 2.6-fold decrease in intracellular XPA mRNA in transgenic MCF-7 cells overexpressing HMGA1 proteins compared with non-HMGA1-expressing cells. XPA protein levels are also similar to 3-fold lower in HMGA1-expressing MCF-7 cells. Moreover, whereas a > 2-fold induction of XPA proteins is observed in normal MCF-7 cells 30 min after UV exposure, no apparent induction of XPA protein is observed in MCF-7 cells expressing HMGA1. Mechanistically, we present both chromatin immunoprecipitation and promoter site-specific mutagenesis evidence linking HMGA1 to repression of XPA transcription via binding to a negative regulatory element in the endogenous XPA gene promoter. Phenotypically, HMGA1-expressing cells exhibit compromised removal of cyclobutane pyrimidine dimer lesions, a characteristic of cells that express low levels of XPA. Importantly, we show that restoring expression of wild-type XPA in HMGA1-expressing cells rescues LTV resistance comparable with that of normal MCF-7 cells. Together, these data provide strong experimental evidence that HMGA1 proteins are. involved in inhibiting XPA expression, resulting in increased UV sensitivity in cells that overexpress these proteins. Because HMGA1 proteins are overexpressed in most naturally occurring cancers, with increasing cellular concentrations correlating with increasing metastatic potential and poor patient prognosis, the current findings provide new insights into previously unsuspected mechanisms contributing to tumor progression.