Pivotal role of inosine triphosphate pyrophosphatase in maintaining genome stability and the prevention of apoptosis in human cells.
Pivotal role of inosine triphosphate pyrophosphatase in maintaining genome stability and the prevention of apoptosis in human cells.
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DOI：
10.1371/journal.pone.0032313
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pavlov YI
中科院分区：
文献类型：
--
作者：
Menezes MR;Waisertreiger IS;Lopez-Bertoni H;Luo X;Pavlov YI
纯净的核苷酸前体池是高保真DNA复制、抑制突变和致癌的先决条件。ITPase是一种核苷三磷酸焦磷酸酶，用于清除非典型的三磷酸肌苷和黄嘌呤的前体。由ITPA基因编码的人类ITPase的确切作用尚不清楚。ITPA在临床上很重要，因为广泛存在的94C>；A多态导致红细胞中ITPase活性为零，并与硫代嘌呤类药物的不良反应有关。我们用嘌呤类似物6-N羟氨基嘌呤(HAP)研究了ITPA在HeLa细胞中的细胞功能，HAP的三磷酸也是ITPA的底物。在这项研究中，我们证明了ITPA基因敲除使HeLa细胞对HAP诱导的DNA断裂和凋亡敏感。在ITPA基因敲除细胞中观察到的HAP诱导的DNA损伤和细胞毒性是由HAM1基因编码的酵母ITPase的过表达所挽救的。我们进一步证明，ITPA基因敲除导致了对HAP处理的高度突变。我们的研究揭示了ITPA在防止碱基类似物诱导的人类细胞凋亡、DNA损伤和突变方面的重要意义。这意味着ITPase缺陷的个体容易受到核苷酸池中的杂质造成的基因组损伤，这种损伤通过使用嘌呤类似物的治疗而大大增加。他们患退行性疾病和癌症的风险也很高。
Pure nucleotide precursor pools are a prerequisite for high-fidelity DNA replication and the suppression of mutagenesis and carcinogenesis. ITPases are nucleoside triphosphate pyrophosphatases that clean the precursor pools of the non-canonical triphosphates of inosine and xanthine. The precise role of the human ITPase, encoded by the ITPA gene, is not clearly defined. ITPA is clinically important because a widespread polymorphism, 94C>A, leads to null ITPase activity in erythrocytes and is associated with an adverse reaction to thiopurine drugs. We studied the cellular function of ITPA in HeLa cells using the purine analog 6-N hydroxylaminopurine (HAP), whose triphosphate is also a substrate for ITPA. In this study, we demonstrate that ITPA knockdown sensitizes HeLa cells to HAP-induced DNA breaks and apoptosis. The HAP-induced DNA damage and cytotoxicity observed in ITPA knockdown cells are rescued by an overexpression of the yeast ITPase encoded by the HAM1 gene. We further show that ITPA knockdown results in elevated mutagenesis in response to HAP treatment. Our studies reveal the significance of ITPA in preventing base analog-induced apoptosis, DNA damage and mutagenesis in human cells. This implies that individuals with defective ITPase are predisposed to genome damage by impurities in nucleotide pools, which is drastically augmented by therapy with purine analogs. They are also at an elevated risk for degenerative diseases and cancer.
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DOI：
10.1073/pnas.45.4.622
发表时间：
1959-01-01
期刊：
PROC NATL ACAD SCI
影响因子：
--
作者：
FREESE, E.
通讯作者：
FREESE, E.
DOI：
10.1016/0027-5107(91)90157-j
发表时间：
1991-09-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
AMES, BN;GOLD, LS
通讯作者：
GOLD, LS
影响因子：
8
作者：
Brem, R.;Li, F.;Montaner, B.;Reelfs, O.;Karran, P.
通讯作者：
Karran, P.
影响因子：
3.6
作者：
Bradshaw, JS;Kuzminov, A
通讯作者：
Kuzminov, A
影响因子：
1.3
作者：
Bakker, Jaap A.;Lindhout, Martijn;Bierau, Jorgen
通讯作者：
Bierau, Jorgen