Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple a-ketoglutarate (a-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of a-KG to broadly inhibit the activity of a-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple a-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.[Keywords: FH; SDH; metabolites; a-KG-dependent dioxygenases; DNA methylation; histone methylation] Supplemental material is available for this article. Received March 7, 2012; revised version accepted May 9, 2012. Several lines of evidence, including the recent identification of mutations affecting isocitrate dehydrogenase (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), have demonstrated that mutations in certain metabolic enzymes may play a causal role in tumorigenesis. The NADP + -dependent IDH genes IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008),

Arbuscular mycorrhizal (AM) fungi facilitate plant uptake of mineral nutrients and draw organic nutrients from the plant. Organic nutrients are thought to be supplied primarily in the form of sugars. Here we show that the AM fungus is a fatty acid auxotroph and that fatty acids synthesized in the host plants are transferred to the fungus to sustain mycorrhizal colonization. The transfer is dependent on RAM2 (REQUIRED FOR ARBUSCULAR MYCORRHIZATION 2) and the ATP binding cassette transporter-mediated plant lipid export pathway. We further show that plant fatty acids can be transferred to the pathogenic fungus and are required for colonization by pathogens. We suggest that the mutualistic mycorrhizal and pathogenic fungi similarly recruit the fatty acid biosynthesis program to facilitate host invasion.

Viroids and most viral satellites have small, noncoding, and highly structured RNA genomes. How they cause disease symptoms without encoding proteins and why they have characteristic secondary structures are two longstanding questions. Recent studies have shown that both viroids and satellites are capable of inducing RNA silencing, suggesting a possible role of this mechanism in the pathology and evolution of these subviral RNAs. Here we show that preventing RNA silencing in tobacco, using a silencing suppressor, greatly reduces the symptoms caused by the Y satellite of cucumber mosaic virus. Furthermore, tomato plants expressing hairpin RNA, derived from potato spindle tuber viroid, developed symptoms similar to those of potato spindle tuber viroid infection. These results provide evidence suggesting that viroids and satellites cause disease symptoms by directing RNA silencing against physiologically important host genes. We also show that viroid and satellite RNAs are significantly resistant to RNA silencing-mediated degradation, suggesting that RNA silencing is an important selection pressure shaping the evolution of the secondary structures of these pathogens.V iroids and most viral satellites, which are the smallest known infectious agents in plants, have single-stranded RNA genomes of 200-400 nt and do not encode proteins (1-3). Whereas viroids replicate autonomously by using host-encoded RNA polymerase, satellite RNAs multiply only in the presence of a helper virus that provides the appropriate RNA-dependent RNA polymerase (2, 4). Intriguingly, some viroids and satellites can induce unique, highly host species-specific disease symptoms despite their exceedingly small size and lack of mRNA activity. Previous studies have shown that one, or a few, nucleotide changes in their RNA genomes can dramatically alter the virulence of these subviral RNAs or the host-plant specificity of the disease symptoms (5-7). Despite intensive investigation, major questions remain as to how these minor sequence variations modulate viroid and satellite pathology and how host plants develop symptoms in response to specific sequences. A striking similarity among viroids and small satellites is that they tend to form characteristic secondary structures due to intramolecular base-pairing. These structures are clearly important, because the evolution of these small RNAs appears to be constrained by the need to preserve their distinct structural features. However, the host factor(s) that imposes this evolutionary pressure has yet to be identified.RNA silencing is a sequence-specific RNA degradation process directed by double-stranded RNA (dsRNA) or selfcomplementary hairpin RNA (hpRNA). This dsRNA or hpRNA is cleaved by an RNase III-like enzyme known as Dicer to generate small (21-to 25-nt) RNAs, termed small interfering RNAs (siRNAs), which are used to guide siRNAribonuclease complexes [known as RNA-induced silencing complexes (RISC)] to degrade cognate single-stranded RNA (8). Recent studies have shown that plants infected with pota...