It has been widely accepted that DNA can adopt other biologically relevant structures beside the Watson-Crick double helix. One recent important example is the guanine-quadruplex (Gquadruplex) structure formed by guanine tracts found in the MYC (or c-myc) promoter region, which regulates the transcription of the MYC oncogene. Stabilization of this G-quadruplex by ligands, such as the cationic porphyrin TMPyP4, decreases the transcriptional level of MYC. Here, we report the first structure of a DNA fragment containing five guanine tracts from this region. An unusual G-quadruplex fold, which was derived from NMR restraints using unambiguous modelindependent resonance assignment approaches, involves a core of three stacked guanine tetrads formed by four parallel guanine tracts with all anti guanines and a snapback 3′-end syn guanine. We have determined the structure of the complex formed between this G-quadruplex and TMPγP4. This structural information, combined with details of small-molecule interaction, provides a platform for the design of anticancer drugs targeting multi-guanine-tract sequences that are found in the MYC and other oncogenic promoters, as well as in telomeres.Human c-MYC is a transcription factor that is central to regulation of cell growth, proliferation, differentiation and apoptosis [1][2][3][4] . The MYC (also known as c-myc) gene that encodes this protein is tightly regulated in normal cells and its aberrant overexpression is associated with the progression of many cancers 5 . An important element in the MYC promoter region, termed nuclease-hypersensitivity element III 1 (NHE III 1 ), controls up to 90% of total MYC transcription [6][7][8][9] . Previous studies have suggested that this element, composed of a pyrimidine-rich and a purine-rich strand, may form other structures beyond the canonical B-DNA Watson-Crick duplex 6,8,[10][11][12] . In particular, the 27-nucleotide (nt) purine-rich strand (Pu27) of this element, which contains six guanine tracts (Table 1), forms multiple G-quadruplex structures [12][13][14][15] built from the stacking of G·G·G·G tetrads 16 . Furthermore, the G-quadruplex structure(s) involving four central guanine tracts of Pu27 is biologically relevant, as its destabilization (by guanine-to-adenine mutations) and its Correspondence should be addressed to A.T.P. (phantuan@mskcc.org) or D.J.P. (pateld@mskcc.org). Accession codes. Protein Data Bank codes: The coordinates for the structures of Pu24I and the Pu24I-TMPyP4 complex have been deposited under accession codes 2A5P and 2A5R, respectively. Note: Supplementary information is available on the Nature Chemical Biology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Here we present the structure of a 24-nt five-guanine-tract sequence from the guanine-rich strand of the MYC NHE III 1 in K + solution. The structure represents a unique intramolecular parallel-stranded foldback G-quadruplex, in which a guanine from the 3′ tail is plugged back into the core...

CUG binding protein 1 (CUGBP1) regulates multiple aspects of nuclear and cytoplasmic mRNA processing, with implications for onset of myotonic dystrophy. CUGBP1 harbors three RRM domains and preferentially targets UGU-rich mRNA elements. We report on crystal structures of CUGBP1 RRM1 and tandem RRM1/2 domains bound to RNAs containing tandem UGU(U/G) elements. Both RRM1 in RRM1-RNA and RRM2 in RRM1/2-RNA complexes use similar principles to target UGU(U/G) elements, with recognition mediated by face-to-edge stacking and water-mediated hydrogen bonding networks. The UG step adopts a left-handed Z-RNA conformation, with the syn guanine recognized through Hoogsteen edge-protein backbone hydrogen-bonding interactions. NMR studies on the RRM1/2-RNA complex establish that both RRM domains target tandem UGUU motifs in solution, while filter-binding assays identify a preference for recognition of GU over AU or GC steps. We discuss the implications of CUGBP1-mediated targeting and sequestration of UGU(U/G) elements on pre-mRNA alternative-splicing regulation, translational regulation and mRNA decay.

In the legend to Supplementary Figure 1 online, the second sentence in panel d should read "FADD-deficient Jurkat cells were treated with indicated concentrations (on log scale, in µM) of Nec-1 (1) and Nec-1i (2) for 24 h."