A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions.
A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions.
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对总染色体重排抑制因子的筛选确定了 PLP 在预防 DNA 损伤中的保守作用。
DOI：
10.1371/journal.pgen.0030134
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发表时间：
2007-08
期刊：
影响因子：
4.5
通讯作者：
Durocher, Daniel
中科院分区：
文献类型：
--
作者：
Kanellis, Pamela;Gagliardi, Mark;Banath, Judit P.;Szilard, Rachel K.;Nakada, Shinichiro;Galicia, Sarah;Sweeney, Frederic D.;Cabelof, Diane C.;Olive, Peggy L.;Durocher, Daniel
基因组不稳定是癌细胞的一个特征。肿瘤细胞中普遍存在的一类基因组畸变被称为总染色体重排（GCRs）。gcr包括染色体易位、扩增、倒位、整个染色体臂的缺失和间质缺失。在这里，我们报告了酿酒酵母全基因组筛选的结果，旨在鉴定新的GCR形成抑制因子。发现的最有效的新型GCR抑制因子是BUD16，它是酵母吡哆醛激酶（Pdxk）的基因编码，是代谢吡哆醛5 '磷酸（PLP）的关键酶，PLP是维生素B6的生物活性形式。我们发现Pdxk通过减少细胞周期中DNA损伤的出现而有效地抑制GCR事件。我们还表明，人类细胞中Pdxk的药理抑制导致dsb的产生和DNA损伤检查点的激活。最后，我们的证据表明，PLP缺乏威胁基因组完整性，最有可能通过其在dTMP生物合成中的作用，因为pdxk缺陷细胞在其核DNA中积累尿嘧啶，并且对核糖核苷酸还原酶的抑制敏感。由于Pdxk将饮食与基因组稳定性联系起来，我们的工作支持了膳食微量营养素通过减少DNA损伤的积累来降低癌症风险的假设，并表明微量营养素的消耗可能是防止过度增殖的防御机制的一部分。细胞分裂前必须保证遗传信息的完整性。基因组完整性的丧失与肿瘤发生特别相关，它被认为有助于恶性细胞向完全癌性表型的快速进化。因此，我们必须充分了解细胞如何保持基因组的完整性以及它如何在肿瘤发生过程中丢失。在这项研究中，我们开发了一种测定方法，使我们能够系统地询问出芽酵母酿酒酵母的每个基因，以了解其各自对基因组完整性的贡献。我们报告了9个新基因的鉴定，这些基因在酵母中被删除时增加了基因组不稳定性的比率。令我们惊讶的是，我们发现的其中一个基因编码吡哆醛激酶，它在维生素B6的代谢中起作用。我们发现吡哆醛激酶通过促进膳食维生素B6转化为其生物活性形式吡哆醛5 '磷酸，从而影响基因组的稳定性。我们的工作表明，维生素B6代谢物对维持基因组稳定性至关重要，并支持了一个长期存在的模型，该模型假设维生素B6通过减少基因组重排来降低癌症风险。
Genome instability is a hallmark of cancer cells. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs). GCRs comprise chromosome translocations, amplifications, inversions, deletion of whole chromosome arms, and interstitial deletions. Here, we report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. The most potent novel GCR suppressor identified is BUD16, the gene coding for yeast pyridoxal kinase (Pdxk), a key enzyme in the metabolism of pyridoxal 5′ phosphate (PLP), the biologically active form of vitamin B6. We show that Pdxk potently suppresses GCR events by curtailing the appearance of DNA lesions during the cell cycle. We also show that pharmacological inhibition of Pdxk in human cells leads to the production of DSBs and activation of the DNA damage checkpoint. Finally, our evidence suggests that PLP deficiency threatens genome integrity, most likely via its role in dTMP biosynthesis, as Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase. Since Pdxk links diet to genome stability, our work supports the hypothesis that dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation. Cells must ensure the integrity of genetic information before cellular division. Loss of genome integrity is particularly germane to tumorigenesis, where it is thought to contribute to the rapid evolution of the malignant cell towards the fully cancerous phenotype. It is therefore imperative that we understand fully how cells maintain the integrity of the genome and how it is lost during tumorigenesis. In this study, we developed an assay that allowed us to systematically interrogate each gene of the budding yeast S. cerevisiae for its respective contribution to genome integrity. We report the identification of nine novel genes that increase the rate of genome instability in yeast when deleted. To our surprise, one of the genes we identified encodes the enzyme pyridoxal kinase, which acts in the metabolism of vitamin B6. We show that pyridoxal kinase influences genome stability by promoting the conversion of dietary vitamin B6 into its biologically active form, pyridoxal 5′ phosphate. Our work indicates that vitamin B6 metabolites are critical to maintain genome stability and supports a long-standing model, which hypothesizes that vitamin B6 reduces cancer risk by curtailing genome rearrangements.
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影响因子：
10.5
作者：
Admire, A;Shanks, L;Weinert, T
通讯作者：
Weinert, T
影响因子：
64.8
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Bartkova, J;Horejsi, Z;Bartek, J
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Bartek, J
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64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda