HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy.
HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy.
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HMGA2表现出DRP/AP位点的切割活性，并保护癌细胞在化学疗法期间免受DNA破坏诱导的细胞毒性。
DOI：
10.1093/nar/gkp375
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发表时间：
2009-07
影响因子：
14.9
通讯作者：
Dröge P
中科院分区：
文献类型：
--
作者：
Summer H;Li O;Bao Q;Zhan L;Peter S;Sathiyanathan P;Henderson D;Klonisch T;Goodman SD;Dröge P
HMGA蛋白在正常人体细胞中不翻译，但在多能胚胎干细胞和大多数肿瘤中以高拷贝数存在。恶性程度、患者预后指数和HMGA水平之间的相关性已被牢固确立。有趣的是，HMGA 2也存在于对化疗有抗性的罕见肿瘤诱导细胞中。在这里，我们证明，HMGA 1a/B和HMGA 2具有内在的dRP和AP位点切割活动，并在AT钩DNA结合结构域的赖氨酸和精氨酸作为亲核试剂的功能。我们还表明，HMGA 2可以共价捕获在癌细胞的基因组脱碱基位点。通过采用各种基于细胞的测定，我们提供了相关裂解酶活性促进细胞对碱基切除修复（BER）途径靶向的DNA损伤的抗性的证据，并且这种保护与HMGA 2表达水平直接相关。此外，我们证明了人AP核酸内切酶1和HMGA 2在癌细胞中的相互作用，这支持了我们的结论，即HMGA 2可以被纳入细胞BER机制。因此，我们的研究确定了HMGA 2在癌细胞DNA修复中的意想不到的作用，这对疾病诊断和治疗具有重要的临床意义。
HMGA proteins are not translated in normal human somatic cells, but are present in high copy numbers in pluripotent embryonic stem cells and most neoplasias. Correlations between the degree of malignancy, patient prognostic index and HMGA levels have been firmly established. Intriguingly, HMGA2 is also found in rare tumor-inducing cells which are resistant to chemotherapy. Here, we demonstrate that HMGA1a/b and HMGA2 possess intrinsic dRP and AP site cleavage activities, and that lysines and arginines in the AT-hook DNA-binding domains function as nucleophiles. We also show that HMGA2 can be covalently trapped at genomic abasic sites in cancer cells. By employing a variety of cell-based assays, we provide evidence that the associated lyase activities promote cellular resistance against DNA damage that is targeted by base excision repair (BER) pathways, and that this protection directly correlates with the level of HMGA2 expression. In addition, we demonstrate an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, which supports our conclusion that HMGA2 can be incorporated into the cellular BER machinery. Our study thus identifies an unexpected role for HMGA2 in DNA repair in cancer cells which has important clinical implications for disease diagnosis and therapy.
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影响因子：
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