NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals.
NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals.
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DOI：
10.1093/nar/gkp1250
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发表时间：
2010-05
影响因子：
14.9
通讯作者：
Nakabeppu Y
中科院分区：
文献类型：
--
作者：
Abolhassani N;Iyama T;Tsuchimoto D;Sakumi K;Ohno M;Behmanesh M;Nakabeppu Y
ITPA基因编码的哺乳动物肌苷三磷酸酶可水解ITP和dITP为单磷酸，避免其有害作用。Itpa−小鼠表现出围产期致死性，在Itpa−胚胎中检测到细胞RNA中肌苷和核DNA中脱氧肌苷的水平显著高于野生型胚胎。因此，我们研究了ITPA缺乏对小鼠胚胎成纤维细胞（MEFs）的影响。与从野生型胚胎制备的初级MEFs相比，缺乏ITP水解活性的Itpa-初级MEFs表现出延长的倍增时间，增加的染色体异常和核DNA中单链断裂的积累。然而，永生化Itpa− MEFs没有这些表型，并且比Itpa−胚胎或初级MEFs具有显著更高的ITP/IDP水解活性。哺乳动物NUDT 16蛋白表现出很强的dIDP/IDP水解活性，并且在来自野生型和Itpa−胚胎的原代MEFs中检测到类似的低水平Nudt 16 mRNA和蛋白。然而，永生化的Itpa-MEFs表达的Nudt 16水平显著高于野生型。此外，将针对Nudt 16的沉默RNA引入永生化的Itpa-MEFs中，再现了ITPA缺陷型表型。因此，我们得出结论，NUDT 16和ITPA发挥双重保护作用，消除dIDP/IDP和dITP/ITP的核苷酸池在哺乳动物。
Mammalian inosine triphosphatase encoded by ITPA gene hydrolyzes ITP and dITP to monophosphates, avoiding their deleterious effects. Itpa− mice exhibited perinatal lethality, and significantly higher levels of inosine in cellular RNA and deoxyinosine in nuclear DNA were detected in Itpa− embryos than in wild-type embryos. Therefore, we examined the effects of ITPA deficiency on mouse embryonic fibroblasts (MEFs). Itpa− primary MEFs lacking ITP-hydrolyzing activity exhibited a prolonged doubling time, increased chromosome abnormalities and accumulation of single-strand breaks in nuclear DNA, compared with primary MEFs prepared from wild-type embryos. However, immortalized Itpa− MEFs had neither of these phenotypes and had a significantly higher ITP/IDP-hydrolyzing activity than Itpa− embryos or primary MEFs. Mammalian NUDT16 proteins exhibit strong dIDP/IDP-hydrolyzing activity and similarly low levels of Nudt16 mRNA and protein were detected in primary MEFs derived from both wild-type and Itpa− embryos. However, immortalized Itpa− MEFs expressed significantly higher levels of Nudt16 than the wild type. Moreover, introduction of silencing RNAs against Nudt16 into immortalized Itpa− MEFs reproduced ITPA-deficient phenotypes. We thus conclude that NUDT16 and ITPA play a dual protective role for eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals.
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影响因子：
5.4
作者：
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通讯作者：
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通讯作者：
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作者：
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通讯作者：
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