Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response.
Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response.
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DOI：
10.1371/journal.pbio.1000328
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发表时间：
2010-03-09
期刊：
影响因子：
9.8
通讯作者：
Pines O
中科院分区：
文献类型：
--
作者：
Yogev O;Yogev O;Singer E;Shaulian E;Goldberg M;Fox TD;Pines O
在DNA损伤时，线粒体酶的胞质形式的线粒体酶转移到细胞核中，在那里，凭借其酶活性，它参与细胞对DNA损伤的反应。这可能解释了其作为肿瘤抑制剂的已知作用。在真核生物中，脱氢酶（FH）是线粒体基质中的一种众所周知的三羧酸循环酶。然而，从酵母到人类的保守是一种胞质同工酶，其在该隔室中的功能仍然不清楚。几年前，FH令人惊讶地被证明是肿瘤易感性综合征，遗传性平滑肌瘤病和肾细胞癌（HLRCC）的基础。在几乎所有的HLRCC肿瘤中都检测到FH的双等位基因失活，因此FH被认为是肿瘤抑制因子。最近有人提出，FH抑制导致细胞内富马酸盐升高，富马酸盐反过来又充当HPH（HIF脯氨酰羟化酶）的竞争性抑制剂，从而通过防止蛋白酶体降解而引起HIF（缺氧诱导因子）的稳定。转录因子HIF增加血管生成调节基因如VEGF的表达，这可导致高微血管密度和肿瘤发生。然而，这一机制并不能完全解释大细胞溶质群体的脱氢酶分子。我们构建了一个酵母菌株，其中的脱氢酶只定位于线粒体。这导致了发现酵母胞质内肽酶在保护细胞免受DNA损伤，特别是DNA双链断裂中起关键作用。我们表明，胞浆中的脱氢酶是一个成员的DNA损伤反应，是从细胞质招募到细胞核后，DNA损伤诱导。反丁烯二酸酶的这种功能取决于其酶活性，并且其在细胞中的缺失可以通过高浓度的反丁烯二酸来补充。我们的研究结果表明，脱氢酶和富马酸是DNA损伤反应的关键因素，这是脱氢酶在人类细胞中的肿瘤抑制作用的基础，并且很可能是HIF独立的。这项研究显示了一个令人兴奋的初级代谢和DNA损伤反应之间的串扰，从而提供了一个方案的肿瘤传播的代谢控制。富马酸水合酶（FH;也称为脱氢酶）是在所有真核生物的细胞质和线粒体中发现的酶。在线粒体中，FH参与通过称为克雷布斯循环的代谢途径为细胞产生能量。然而，它在细胞质中的作用尚不清楚。FH可以作为肿瘤抑制因子发挥作用：它的缺失与称为HLRCC的综合征中人类肾脏肿瘤的形成有关。我们在这里表明，FH的细胞质版本在修复细胞核中的DNA双链断裂中具有意想不到的作用。这种作用涉及FH从细胞质进入细胞核的运动，并取决于其酶活性。引人注目的是，当FH在细胞中缺失时，它在DNA修复中的功能可以被高浓度的酶产物之一富马酸所取代。我们的研究结果表明，FH缺乏导致癌症，因为细胞核中没有足够的富马酸来刺激DNA双链断裂的修复;这些断裂的持续存在被认为会引发癌症。因此，这项研究在初级代谢和细胞对DNA损伤的反应之间建立了令人惊讶的联系。
Upon DNA damage, a cytosolic form of the mitochondrial enzyme fumarase moves into the nucleus where, by virtue of its enzymatic activity, it participates in the cell's response to DNA damage. This potentially explains its known role as a tumor suppressor. In eukaryotes, fumarase (FH in human) is a well-known tricarboxylic-acid-cycle enzyme in the mitochondrial matrix. However, conserved from yeast to humans is a cytosolic isoenzyme of fumarase whose function in this compartment remains obscure. A few years ago, FH was surprisingly shown to underlie a tumor susceptibility syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). A biallelic inactivation of FH has been detected in almost all HLRCC tumors, and therefore FH was suggested to function as a tumor suppressor. Recently it was suggested that FH inhibition leads to elevated intracellular fumarate, which in turn acts as a competitive inhibitor of HPH (HIF prolyl hydroxylase), thereby causing stabilization of HIF (Hypoxia-inducible factor) by preventing proteasomal degradation. The transcription factor HIF increases the expression of angiogenesis regulated genes, such as VEGF, which can lead to high microvessel density and tumorigenesis. Yet this mechanism does not fully explain the large cytosolic population of fumarase molecules. We constructed a yeast strain in which fumarase is localized exclusively to mitochondria. This led to the discovery that the yeast cytosolic fumarase plays a key role in the protection of cells from DNA damage, particularly from DNA double-strand breaks. We show that the cytosolic fumarase is a member of the DNA damage response that is recruited from the cytosol to the nucleus upon DNA damage induction. This function of fumarase depends on its enzymatic activity, and its absence in cells can be complemented by high concentrations of fumaric acid. Our findings suggest that fumarase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarase in human cells and which is most probably HIF independent. This study shows an exciting crosstalk between primary metabolism and the DNA damage response, thereby providing a scenario for metabolic control of tumor propagation. Fumarate hydratase (FH; also known as fumarase) is an enzyme found in both the cytoplasm and mitochondria of all eukaryotes. In mitochondria, FH is involved in generating energy for the cell through a metabolic pathway called the Krebs cycle. Its role in the cytoplasm, however, is unclear. FH can function as a tumor suppressor: its absence is linked to the formation of human kidney tumors in a syndrome termed HLRCC. We show here that the cytoplasmic version of FH has an unexpected role in repairing DNA double-strand breaks in the nucleus. This role involves the movement of FH from the cytoplasm into the nucleus and depends on its enzymatic activity. Strikingly, when FH is absent from cells, its function in DNA repair can be substituted by high concentrations of one of the enzyme's products, fumaric acid. Our findings imply that FH deficiency leads to cancer because there is not enough fumaric acid in the nucleus to stimulate repair of DNA double-strand breaks; the persistence of these breaks is believed to provoke cancer. The study thus makes a surprising connection between primary metabolism and the cell's response to DNA damage.
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DOI：
10.1016/j.bbadis.2008.01.008
发表时间：
2008-05-01
影响因子：
6.2
作者：
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