Also published as: Ao Song, BL Song, Bin Song, C Song, C. Song, D.F. Song, DJ Song, DK Song, Dongfan Song, EJ Song, G. S. Song, H. O. Song, H.H. Song, H.S. Song, HK Song, HS Song, Hai-Bin Song, Hui Song, I-S Song, J Song, J. Song, J.B. Song, J.Y. Song, JX Song, JY Song, Ji Inn Song, Jiaqi Song, Jiaxing Song, Jimyeong Song, Jinglin Song, Junke Song, K. W. Y. Song, K.-J. Song, KH Song, L Song, LX Song, Lijiang Song, Lina Song, Linna Song, M Song, MY Song, Minmin Song, Moon-Young Song, Q.X. Song, R. L. Song, Ruifeng Song, S Song, S. M. Song, Sihui Song, Siyi Song, T Song, T. Song, W Song, Weijie Song, Woon Ju Song, X Song, X. Song, XL Song, Xing-Dong Song, Y. Song, Y.J. Song, Y.S. Song, Yang Song, Ying Song, Youngdong Song, Yunjia Song, Z Song, Z.K. Song
N6-methyladenosine (m6A) serves as a major RNA methylation modification and impacts the initiation and progression of various human cancers through diverse mechanisms. It has been reported that m6A RN Show more
N6-methyladenosine (m6A) serves as a major RNA methylation modification and impacts the initiation and progression of various human cancers through diverse mechanisms. It has been reported that m6A RNA methylation is involved in different physiological and pathological processes, including stem cell differentiation and motility, immune response, cellular stress, tissue renewal and viral infection. In this review, the m6A modification and its regulatory functions in a few major cancers is introduced. The detection approaches for the m6A sites identification are discussed. Additionally, the potential of the RNA m6A modification in clinical application is discussed. Show less
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss Show more
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-Goutières Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons. Show less
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called th Show more
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called the mitochondrial calcium
uniporter. Here, we determined the structures of the pore-forming MCU proteins
by X-ray crystallography and single-particle cryo-electron microscopy. The
stoichiometry, overall architecture, and individual subunit structure differed
markedly from those in the recent nuclear magnetic resonance structure of the
Caenorhabditis elegans MCU. In our studies, we observed a dimer-of-dimer
architecture across species and chemical environments, which was corroborated by
biochemical experiments. Structural analyses and functional characterizations
uncovered the roles of critical residues in the pore. These results reveal a new
ion channel architecture, provide insights into calcium coordination,
selectivity, and conduction, and establish a structural framework for
understanding the mechanism of mitochondrial calcium uniporter function. Show less
The human nucleotide excision repair system targets a wide variety of DNA adducts for removal from DNA, including photoproducts induced by UV wavelengths of sunlight. A key feature of nucleotide excis Show more
The human nucleotide excision repair system targets a wide variety of DNA adducts for removal from DNA, including photoproducts induced by UV wavelengths of sunlight. A key feature of nucleotide excision repair is its dual incision mechanism, which results in generation of a small, damage-containing oligonucleotide approximately 24 to 32 nt in length. Detection of these excised oligonucleotides using cell-free extracts and purified proteins with defined DNA substrates has provided a robust biochemical assay for excision repair activity in vitro. However, the relevance of a number of in vitro findings to excision repair in living cells in vivo has remained unresolved. Over the past few years, novel methods for detecting and isolating the excised oligonucleotide products of repair in vivo have therefore been developed. Here we provide a basic outline of a sensitive and versatile in vivo excision assay and discuss how the assay both confirms previous in vitro findings and offers a number of advantages over existing cell-based DNA repair assays. Thus, the in vivo excision assay offers a powerful tool for readily monitoring the repair of DNA lesions induced by a large number of environmental carcinogens and anticancer compounds. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored Show more
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less
Ga Young Park, Justin J Wilson, Ying Song+1 more · 2012 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-20
Monofunctional platinum(II) complexes of general formula cis-[Pt(NH(3))(2)(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these c Show more
Monofunctional platinum(II) complexes of general formula cis-[Pt(NH(3))(2)(N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH(3))(2)(phenanthridine)Cl]NO(3), which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5'-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. Show less
To overcome drug resistance and reduce the side effects of cisplatin, a widely used antineoplastic agent, major efforts have been made to develop next generation platinum-based anticancer drugs. Becau Show more
To overcome drug resistance and reduce the side effects of cisplatin, a widely used antineoplastic agent, major efforts have been made to develop next generation platinum-based anticancer drugs. Because cisplatin-DNA adducts block RNA polymerase II unless removed by transcription-coupled excision repair, compounds that react similarly but elude repair are desirable. The monofunctional platinum agent pyriplatin displays antitumor activity in mice, a cytotoxicity profile in cell cultures distinct from that of cisplatin, and a unique in vitro transcription inhibition mechanism. In this study, we incorporated pyriplatin globally or site specifically into luciferase reporter vectors to examine its transcription inhibition profiles in live mammalian cells. Monofunctional pyriplatin reacted with plasmid DNA as efficiently as bifunctional cisplatin and inhibited transcription as strongly as cisplatin in various mammalian cells. Using repair-defective nucleotide excision repair (NER)-, mismatch repair-, and single-strand break repair-deficient cells, we show that NER is mainly responsible for removal of pyriplatin-DNA adducts. These findings reveal that the mechanism by which pyriplatin generates its antitumor activity is very similar to that of cisplatin, despite the chemically different nature of their DNA adducts, further supporting a role for monofunctional platinum anticancer agents in human cancer therapy. This information also provides support for the validity of the proposed mechanism of action of cisplatin and provides a rational basis for the design of more potent platinum anticancer drug candidates using a monofunctional DNA-damaging strategy. Show less
In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution Show more
In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution of Pt(II) complexes results in significant platination of RNA, and localization studies find Pt(II) in the nucleus, nucleolus, and a distribution of other sites in cells. Treatment with Pt(II) compounds disrupts RNA-based processes including enzymatic processing, splicing, and translation, and this disruption may be indicative of structural changes to RNA or RNA-protein complexes. Several RNA-Pt(II) adducts have been characterized in vitro by biochemical and other methods. Evidence for Pt(II) binding in non-helical regions and for Pt(II) cross-linking of internal loops has been found. Although platinated sites have been identified, there currently exists very little in the way of detailed structural characterization of RNA-Pt(II) adducts. Some insight into the details of Pt(II) coordination to RNA, especially RNA helices, can be gained from DNA model systems. Many RNA structures, however, contain complex tertiary folds and common, purine-rich structural elements that present suitable Pt(II) nucleophiles in unique arrangements which may hold the potential for novel types of platinum-RNA adducts. Future research aimed at structural characterization of platinum-RNA adducts may provide further insights into platinum-nucleic acid binding motifs, and perhaps provide a rationale for the observed inhibition by Pt(II) complexes of splicing, translation, and enzymatic processing. Show less
The first bis(BF(2)) core complex containing a 1,8-naphthyridin derivative (1,2-bis(5,7-dimethyl-1,8-naphthyridin-2-yl)hydrazine) and with yellow-green emission as well as a high quantum yield was syn Show more
The first bis(BF(2)) core complex containing a 1,8-naphthyridin derivative (1,2-bis(5,7-dimethyl-1,8-naphthyridin-2-yl)hydrazine) and with yellow-green emission as well as a high quantum yield was synthesized and structurally characterized, and the compound exhibits two-photon absorption and excited fluorescence properties. Show less
The quinone/semiquinone/hydroquinone triad (Q/SQ(*-)/H(2)Q) represents a class of compounds that has great importance in a wide range of biological processes. The half-cell reduction potentials of the Show more
The quinone/semiquinone/hydroquinone triad (Q/SQ(*-)/H(2)Q) represents a class of compounds that has great importance in a wide range of biological processes. The half-cell reduction potentials of these redox couples in aqueous solutions at neutral pH, E degrees ', provide a window to understanding the thermodynamic and kinetic characteristics of this triad and their associated chemistry and biochemistry in vivo. Substituents on the quinone ring can significantly influence the electron density "on the ring" and thus modify E degrees' dramatically. E degrees' of the quinone governs the reaction of semiquinone with dioxygen to form superoxide. At near-neutral pH the pK(a)'s of the hydroquinone are outstanding indicators of the electron density in the aromatic ring of the members of these triads (electrophilicity) and thus are excellent tools to predict half-cell reduction potentials for both the one-electron and two-electron couples, which in turn allow estimates of rate constants for the reactions of these triads. For example, the higher the pK(a)'s of H(2)Q, the lower the reduction potentials and the higher the rate constants for the reaction of SQ(*-) with dioxygen to form superoxide. However, hydroquinone autoxidation is controlled by the concentration of di-ionized hydroquinone; thus, the lower the pK(a)'s the less stable H(2)Q to autoxidation. Catalysts, e.g., metals and quinone, can accelerate oxidation processes; by removing superoxide and increasing the rate of formation of quinone, superoxide dismutase can accelerate oxidation of hydroquinones and thereby increase the flux of hydrogen peroxide. The principal reactions of quinones are with nucleophiles via Michael addition, for example, with thiols and amines. The rate constants for these addition reactions are also related to E degrees'. Thus, pK(a)'s of a hydroquinone and E degrees ' are central to the chemistry of these triads. Show less