Also published as: AJ Wu, B Wu, Bi-Wen Wu, C Wu, C-H Wu, C. H. Wu, C. Wu, CJ Wu, CL Wu, CW Wu, CY Wu, Chao Wu, Chengnan Wu, Chia-Hua Wu, D Wu, D. Wu, Danny Wu, Dong-Dong Wu, Dongliang Wu, E. L. Wu, E. M. Wu, F Wu, F. F. Wu, FF Wu, Fenglin Wu, Fu-Hai Wu, G Wu, G. Wu, G.S. Wu, GS Wu, Gang Wu, H Wu, H. Wu, Hai-Feng Wu, Hong Wu, J Wu, J. Wu, Jia Wu, Jiabin Wu, Jian Hui Wu, Jian Wu, Jie Wu, Judy I-Chia Wu, Judy I. Wu, K Wu, Kunwei Wu, L Wu, L. F. Wu, L. Wu, L.W. Wu, LL Wu, Lani F Wu, Lei Wu, Li-Bin Wu, Lirong Wu, Liyan Wu, M Wu, M. A. Wu, M. Wu, MJ Wu, Meng Wu, Min Wu, Min-Song Wu, N. Wu, Nan Wu, P Wu, PH Wu, Q Wu, Q. Wu, QJ Wu, Qi Wu, Qin Wu, Qiong Wu, R Wu, S Wu, S. R. Wu, S. Wu, S.D. Wu, SY Wu, Shijia Wu, Shiqi Wu, Shourong Wu, T Wu, T. Wu, T.-F. Wu, T.F. Wu, Tong Wu, Tongde Wu, W Wu, W. Wu, W.-J. Wu, W.J. Wu, Wei-Li Wu, Wenping Wu, X Wu, X. Wu, Xianbo Wu, Xiang Wu, Xiao-Chao Wu, Xiao-Hui Wu, Xiaohua Wu, Xiuwen Wu, Xue-Yu Wu, Y Wu, Y. Wu, Y.B. Wu, YC Wu, YY Wu, Yanping Wu, Yanyu Wu, Yao Wu, Yi Wu, Yibing Wu, Yong Wu, Yunkun Wu, Yunyi Wu, Yuqi Wu, Yuting Wu, Z Wu, Z. Wu, Z.Y. Wu, Zhaofei Wu, Zhi-Zhong Wu, Zhili Wu, Zijun Wu
Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to t Show more
Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction. Show less
A palladium(II)-catalyzed asymmetric 1,2-diamination of 1,3-dienes with readily available dialkylureas was established by using a chiral pyridine-oxazoline ligand. The diamination reaction exclusively Show more
A palladium(II)-catalyzed asymmetric 1,2-diamination of 1,3-dienes with readily available dialkylureas was established by using a chiral pyridine-oxazoline ligand. The diamination reaction exclusively occurs at the terminal C-C double bond of the 1,3-dienes to give 4-vinylimidazolidin-2-ones in high yields and with excellent levels of enantioselectivity (up to 99% yield, 97% ee). The reaction could feasibly be applied for gram-scale synthesis with a 1:1 ratio of the diene and the urea. Show less
AbstractThe 2‐(1,2,3‐triazol‐4‐yl)pyridine motif, with its facile “click” synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal‐directed self‐assembl Show more
AbstractThe 2‐(1,2,3‐triazol‐4‐yl)pyridine motif, with its facile “click” synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal‐directed self‐assembly of intricate three‐dimensional structures. Organic ligands that bear two such chelates bridged by flexible hinge moieties readily undergo self‐assembly with metal ions of different coordination geometries to generate a series of topologically diverse metallomacrocycles that can be used for numerous applications. Herein, the synthesis and self‐assembly of one such ligand with zinc(II), copper(II), and palladium(II) ions is reported, and the stability of the resulting metallomacrocycles described. An investigation into the use of these metallomacrocycles for the recognition of both small‐molecule substrates, such as deoxyguanosine monophosphate, and larger biological assemblies, such as DNA and RNA guanine quadruplexes, is also described. 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
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumour Show more
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts. Show less
Liang Xu, Wei Wang, Jiabin Wu+6 more · 2017 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-20
Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, interfere with the efficiency and accuracy of DNA replication and transcription. However, the molecular mec Show more
Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, interfere with the efficiency and accuracy of DNA replication and transcription. However, the molecular mechanisms of DNA alkylation-induced transcriptional stalling and mutagenesis remain unknown. In this study, we systematically investigated how RNA polymerase II (pol II) recognizes and bypasses regioisomeric O2-, N3-, and O4-ethylthymidine (O2-, N3-, and O4-EtdT) lesions. We observed distinct pol II stalling profiles for the three regioisomeric EtdT lesions. Intriguingly, pol II stalling at O2-EtdT and N3-EtdT sites is exacerbated by TFIIS-stimulated proofreading activity. Assessment for the impact of the EtdT lesions on individual fidelity checkpoints provided further mechanistic insights, where the transcriptional lesion bypass routes for the three EtdT lesions are controlled by distinct fidelity checkpoints. The error-free transcriptional lesion bypass route is strongly favored for the minor-groove O2-EtdT lesion. In contrast, a dominant error-prone route stemming from GMP misincorporation was observed for the major-groove O4-EtdT lesion. For the N3-EtdT lesion that disrupts base pairing, multiple transcriptional lesion bypass routes were found. Importantly, the results from the present in vitro transcriptional studies are well correlated with in vivo transcriptional mutagenesis analysis. Finally, we identified a minor-groove-sensing motif from pol II (termed Pro-Gate loop). The Pro-Gate loop faces toward the minor groove of RNA:DNA hybrid and is involved in modulating the translocation of minor-groove alkylated DNA template after nucleotide incorporation opposite the lesion. Taken together, this work provides important mechanistic insights into transcriptional stalling, lesion bypass, and mutagenesis of alkylated DNA lesions. 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
AbstractWhile NMR and IR spectroscopic signatures and structural characteristics of low‐barrier hydrogen bond (LBHB) formation are well documented in the literature, direct measurement of the LBHB ene Show more
AbstractWhile NMR and IR spectroscopic signatures and structural characteristics of low‐barrier hydrogen bond (LBHB) formation are well documented in the literature, direct measurement of the LBHB energy is difficult. Here, we show that solid‐state 17O NMR spectroscopy can provide unique information about the energy required to break a LBHB. Our solid‐state 17O NMR data show that the HB enthalpy of the O⋅⋅⋅H⋅⋅⋅N LBHB formed in crystalline nicotinic acid is only 7.7±0.5 kcal mol−1, suggesting that not all LBHBs are particularly strong. Show less
Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdo Show more
Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation. Show less
Li-Bin Wu, Wen-Yi Su, Ya-Mei He+3 more · 2015 · Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry · Taylor & Francis · added 2026-05-01
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
In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. De Show more
In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism. Show less
Superoxide anion is the first generated reactive oxygen species (ROS) after oxygen enters living cells. It was once considered to be highly deleterious to cell functions and aging. Therefore, antioxid Show more
Superoxide anion is the first generated reactive oxygen species (ROS) after oxygen enters living cells. It was once considered to be highly deleterious to cell functions and aging. Therefore, antioxidants were suggested to prevent aging and degenerative diseases. However, superoxide signaling has been shown in many physiological responses such as transcriptional regulation, protein activation, bioenergy output, cell proliferation and apoptosis. The uncoupling proteins (UCPs) are a family of mitochondrial anion-carrier proteins located in the inner mitochondrial membrane and are considered to reduce the generation of superoxide anion through the mitochondrial mild uncoupling. UCPs are important in prevention of mitochondrial excessive generation of ROS, transfer of mitochondrial substrates, mitochondrial calcium uniport and regulation of thermogenesis. Superoxide anion and uncoupling proteins are linked to Alzheimer's disease in mitochondria. Simultaneous disorders of superoxide and uncoupling proteins create the conditions for neuronal oxidative damages. On the one hand, sustained oxidative damage causes neuronal apoptosis and eventually, accumulated neuronal apoptosis, leading to exacerbations of Alzheimer's disease. On the other hand, our study has shown that UCP2 and UCP4 have important impact on mitochondrial calcium concentration of nerve cells, suggesting that their abnormal expression may involve in the pathogenesis of Alzheimer's disease. Show less
Mitochondrial dysfunction, which is closely related to intracellular calcium overload and excessive free radicals, is an important cause of Alzheimer's disease (AD). However, molecular mechanisms of t Show more
Mitochondrial dysfunction, which is closely related to intracellular calcium overload and excessive free radicals, is an important cause of Alzheimer's disease (AD). However, molecular mechanisms of the mitochondrial Ca(2+) disregulation induced by oxidative stress in AD are still obscure. In an effort to gain a further understanding of this problem, we investigated the effects of superoxide anion, a primary free radical, on the expression of uncoupling proteins (UCPs) and the mitochondrial free Ca(2+) levels in the neuroblastoma SH-SY5Y cell line (neo) and stably expressed wild-type human APP(APP) and APP-Swedish mutation (APPsw) SH-SY5Y cells. It was found that UCP2 and UCP4 protein levels were upregulated in neo but downregulated in APP and APPsw cells by the superoxide anion. Our results show that the superoxide anion can regulate protein levels of UCP2 and UCP4 in SH-SY5Y cells, and the mitochondrial free Ca(2+) shifted their levels, tightly coupled with the protein levels of UCPs. When UCP2 and UCP4 were knocked down by siRNA, the result was reversed. These data suggest that the superoxide anion can regulate the mitochondrial free Ca(2+) by regulating the expression of UCPs. These observations also indicate that UCPs can be potential targets in pathotherapy prevention of AD. Show less
The cytotoxicity of platinum compounds is thought to be determined primarily by their DNA adducts. Cisplatin and oxaliplatin are structurally distinct, but form the same types of adducts at the same s Show more
The cytotoxicity of platinum compounds is thought to be determined primarily by their DNA adducts. Cisplatin and oxaliplatin are structurally distinct, but form the same types of adducts at the same sites on DNA. However, the DNA adducts are differentially recognized by a number of cellular proteins. For example, mismatch repair proteins and some damage-recognition proteins bind to cisplatin-GG adducts with higher affinity than to oxaliplatin-GG adducts, and this differential recognition of cisplatin- and oxaliplatin-GG adducts is thought to contribute to the differences in cytotoxicity and tumor range of cisplatin and oxaliplatin. A detailed kinetic analysis of the insertion and extension steps of dNTP incorporation in the vicinity of the adduct shows that both DNA polymerase beta (pol beta) and DNA polymerase eta (pol eta) catalyze translesion synthesis past oxaliplatin-GG adducts with greater efficiency than past cisplatin-GG adducts. In the case of pol eta, the efficiency and fidelity of translesion synthesis in vitro is very similar to that previously observed with cyclobutane TT dimers, suggesting that pol eta is likely to be involved in error-free bypass of Pt adducts in vivo. This has been confirmed for cisplatin by comparing the cisplatin-induced mutation frequency in human fibroblast cell lines with and without pol eta. Thus, the greater efficiency of bypass of oxaliplatin-GG adducts by pol eta may explain the lower mutagenicity of oxaliplatin compared to cisplatin. The ability of these cellular proteins to discriminate between cisplatin and oxaliplatin adducts suggest that there exist significant conformational differences between the adducts, yet the crystal structures of the cisplatin- and oxaliplatin-GG adducts were very similar. We have recently solved the solution structure of the oxaliplatin-GG adduct and have shown that it is significantly different from the previously published solution structures of the cisplatin-GG adducts. Furthermore, the observed differences in conformation provide a logical explanation for the differential recognition of cisplatin and oxaliplatin adducts by mismatch repair and damage-recognition proteins. Show less