Also published as: A Xu, B Xu, C Xu, C. M. Xu, C. Xu, Chenxi Xu, D Xu, D. F. Xu, D. Xu, Daqian Xu, Dingguo Xu, F Xu, FX Xu, Feng Xu, G Xu, G. Xu, Gang Xu, Guang‐Xi Xu, H Xu, H. Xu, H.C. Xu, HW Xu, Hao Xu, Hongjiao Xu, Hui-Hua Xu, J Xu, J. Xu, JT Xu, Jijun Xu, Jing Xu, Juan Xu, Jun Xu, K Xu, K. Xu, Ke Xu, L Xu, L. Xu, Liang Xu, Lin Xu, M Xu, N. N. Xu, N. Xu, Na Xu, P. Xu, Pengfei Xu, Q. Xu, Q.-S. Xu, Qi-Jie Xu, Qian Xu, R Xu, R. Xu, S Xu, S. Q. Xu, S. Xu, S.Q. Xu, S.Z. Xu, SG Xu, Shanmei Xu, Shuai Xu, Sun, Xu, T. Xu, W Xu, W. Xu, Wenyuan Xu, X Xu, X.L. Xu, Xiaowei Xu, Xiaowu Xu, Xieyang Xu, Xin Xu, Xingke Xu, Xueli Xu, Y Xu, Y-H Xu, Y. Xu, Yan Xu, Yanjian Xu, Yunjian Xu, Yunli Xu, Z Xu, Z. Xu, Z.K. Xu, ZB Xu, ZG Xu, Zhao, Xu, Zhi Xu, Zhigang Xu, Zhishan Xu, Zhongren Xu, Zichen Xu
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
Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards und Show more
Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards understanding the molecular basis of RNA polymerase II (Pol II) transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. In particular, we will focus on the three key checkpoint steps of controlling Pol II transcriptional fidelity: insertion (specific nucleotide selection and incorporation), extension (differentiation of RNA transcript extension of a matched over mismatched 3'-RNA terminus), and proofreading (preferential removal of misincorporated nucleotides from the 3'-RNA end). We will also discuss some novel insights into the molecular basis and chemical perspectives of controlling Pol II transcriptional fidelity through structural, computational, and chemical biology approaches. Show less
Current precious-metal-containing anticancer agents are mostly chelated with N-containing ligands and function by interacting with DNA. In the present study, Pd(acac)2, a Pd(II) complex containing fou Show more
Current precious-metal-containing anticancer agents are mostly chelated with N-containing ligands and function by interacting with DNA. In the present study, Pd(acac)2, a Pd(II) complex containing four O-donor ligands, has been evaluated as an active anticancer agent. Pd(acac)2 showed no interaction with N-ligand-containing DNA and the S-ligand-containing DMSO, probably because of the two six-member chelate rings that limit the release of the central Pd nuclei to bind to other ligands. Importantly, we found that Pd(acac)2 exhibited better growth inhibitory effects than cisplatin in several cancer cells. Treatment with Pd(acac)2 significantly induced apoptosis in H460 cells. Mechanistically, Pd(acac)2 induced the activation of a series of key components in ER stress-mediated apoptotic pathway, followed by caspase cleavage and activation, while cisplatin showed no similar effects. CHOP knockdown by specific siRNA significantly attenuated Pd(acac)2-induced cell apoptosis. Finally, Pd(acac)2 significantly inhibits H460 cell growth in xenograft mouse models. Taken together, these mechanistic insights on Pd(acac)2 provide us with a novel mechanism and strategy for the development of precious-metal-based anticancer drugs. Show less
The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many effic Show more
The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many efficacious condensing agents have been discovered and investigated, little is known about the conversation of condensation-release under suitable conditions. A novel class of DNA condensing agents based on small azaheterocyclic metal-binding molecules has been discovered and described. Both linear and plasmid DNA can be condensed to nanoparticles by the title compounds with 50 °C incubation, especially in the presence of divalent metal ions. Importantly, this condensation may be released to original forms with little or no damage to the DNA under incubation at physiological temperatures. These changes in DNA morphology over time have been analyzed by gel electrophoresis, circular dichroism (CD), and atomic force microscopy (AFM). The present work might help to develop strategies for the design and synthesis of controllable condensing agents, which may also be applied to control gene expression and delivery. Show less