The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases. The Yes-associated protein (YAP) is a transcriptional coactivator (Yagi et al. 1999). YAP knockout in mice causes embryonic lethality (Morin-Kensicki et al. 2006), indicating its critical role in development. In contrast, transgenic expression of YAP dramatically increases mouse liver size in a reversible fashion (Camargo et al. 2007;Dong et al. 2007), suggesting a key role of YAP in organ size regulation. Consistent with its growth-promoting function, yap genomic amplification and elevated protein levels have been observed in several human cancers (Overholtzer et al. 2006;Zender et al. 2006;Dong et al. 2007;Zhao et al. 2007;Steinhardt et al. 2008). Furthermore, expression of active YAP potently induces transformation in both NIH3T3 and MCF10A cells (Overholtzer et al. 2006;Zhao et al. 2009), and liver-specific transgenic expression of YAP causes tumor formation in vivo (Camargo et al. 2007;Dong et al. 2007). These observations support the function of YAP as a human oncogene.As a transcriptional coactivator, YAP needs to bind transcription factors to stimulate gene expression. Reported YAP target transcription factors include TEAD, p73, Runx2, and the ErbB4 cytoplasmic domain (Yagi et al. 1999;Strano et al. 2001;Vassilev et al. 2001;Komuro et al. 2003). However, only TEAD has been demonstrated to be important for the growth-promoting function of YAP Zhao et al. 2008). In humans, the TEAD family has four highly homologous proteins sharing a conserved DNA-binding TEA domain. YAP and TEAD1 bind to a common set of promoters in MCF10A cells (Zhao et al. 2008). Knockdown of TEAD aborts expression of the majority of YAP-inducible genes and largely attenuates YAP-induced overgrowth, epithelial-mesenchymal transition (EMT), and oncogenic transformation (Zhao et al. 2008). Furthermore, the phenotype of TEAD1/TEAD2 double-knockout mice resembles YAP knockout mice . Notably, the role of the YAP and TEAD complex in growth promotion is implicated in Sveinsson's chorioretinal atrophy caused by the TEAD1 Y406H mutation, which abolishes its interaction with and activation by YAP (Kitagawa 2007;Zhao et al. 2008). Consistently, Scalloped (Sd), the Drosophila homolog of TEAD, directly mediates Yorkie (Yki)-induced gene expression and overgrowth phenotypes (Zhao et al. 2007;Gou...

TET proteins oxidize 5-methylcytosine (5mC) on DNA and play important roles in various biological processes. Mutations of TET2 are frequently observed in myeloid malignance. Here, we present the crystal structure of human TET2 bound to methylated DNA at 2.02 Å resolution. The structure shows that two zinc fingers bring the Cys-rich and DSBH domains together to form a compact catalytic domain. The Cys-rich domain stabilizes the DNA above the DSBH core. TET2 specifically recognizes CpG dinucleotide and shows substrate preference for 5mC in a CpG context. 5mC is inserted into the catalytic cavity with the methyl group orientated to catalytic Fe(II) for reaction. The methyl group is not involved in TET2-DNA contacts so that the catalytic cavity allows TET2 to accommodate 5mC derivatives for further oxidation. Mutations of Fe(II)/NOG-chelating, DNA-interacting, and zinc-chelating residues are frequently observed in human cancers. Our studies provide a structural basis for understanding the mechanisms of TET-mediated 5mC oxidation.

SUMMARY Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1α may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.

As the world’s second largest sand sea and one of the most important dust sources to the global aerosol system, the formation of the Taklimakan Desert marks a major environmental event in central Asia during the Cenozoic. Determining when and how the desert formed holds the key to better understanding the tectonic–climatic linkage in this critical region. However, the age of the Taklimakan remains controversial, with the dominant view being from ∼3.4 Ma to ∼7 Ma based on magnetostratigraphy of sedimentary sequences within and along the margins of the desert. In this study, we applied radioisotopic methods to precisely date a volcanic tuff preserved in the stratigraphy. We constrained the initial desertification to be late Oligocene to early Miocene, between ∼26.7 Ma and 22.6 Ma. We suggest that the Taklimakan Desert was formed as a response to a combination of widespread regional aridification and increased erosion in the surrounding mountain fronts, both of which are closely linked to the tectonic uplift of the Tibetan–Pamir Plateau and Tian Shan, which had reached a climatically sensitive threshold at this time.