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Full-Text Articles in Medical Molecular Biology
Coordination Between Aminoacylation And Editing To Protect Against Proteotoxicity, Hong Zhang, Parker Murphy, Jason Yu, Sukyeong Lee, Francis T F Tsai, Ambro Van Hoof, Jiqiang Ling
Coordination Between Aminoacylation And Editing To Protect Against Proteotoxicity, Hong Zhang, Parker Murphy, Jason Yu, Sukyeong Lee, Francis T F Tsai, Ambro Van Hoof, Jiqiang Ling
Student and Faculty Publications
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that ligate amino acids to tRNAs, and often require editing to ensure accurate protein synthesis. Recessive mutations in aaRSs cause various neurological disorders in humans, yet the underlying mechanism remains poorly understood. Pathogenic aaRS mutations frequently cause protein destabilization and aminoacylation deficiency. In this study, we report that combined aminoacylation and editing defects cause severe proteotoxicity. We show that the ths1-C268A mutation in yeast threonyl-tRNA synthetase (ThrRS) abolishes editing and causes heat sensitivity. Surprisingly, experimental evolution of the mutant results in intragenic mutations that restore heat resistance but not editing. ths1-C268A destabilizes ThrRS and …
Genome-Wide Analysis Of The Interplay Between Chromatin-Associated Rna And 3d Genome Organization In Human Cells, Riccardo Calandrelli, Xingzhao Wen, John Lalith Charles Richard, Zhifei Luo, Tri C Nguyen, Chien-Ju Chen, Zhijie Qi, Shuanghong Xue, Weizhong Chen, Zhangming Yan, Weixin Wu, Kathia Zaleta-Rivera, Rong Hu, Miao Yu, Yuchuan Wang, Wenbo Li, Jian Ma, Bing Ren, Sheng Zhong
Genome-Wide Analysis Of The Interplay Between Chromatin-Associated Rna And 3d Genome Organization In Human Cells, Riccardo Calandrelli, Xingzhao Wen, John Lalith Charles Richard, Zhifei Luo, Tri C Nguyen, Chien-Ju Chen, Zhijie Qi, Shuanghong Xue, Weizhong Chen, Zhangming Yan, Weixin Wu, Kathia Zaleta-Rivera, Rong Hu, Miao Yu, Yuchuan Wang, Wenbo Li, Jian Ma, Bing Ren, Sheng Zhong
Faculty and Staff Publications
The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA …
New Insights Into Rna Processing By The Eukaryotic Trna Splicing Endonuclease, Cassandra K Hayne, Samoil Sekulovski, Jennifer E Hurtig, Robin E Stanley, Simon Trowitzsch, Ambro Van Hoof
New Insights Into Rna Processing By The Eukaryotic Trna Splicing Endonuclease, Cassandra K Hayne, Samoil Sekulovski, Jennifer E Hurtig, Robin E Stanley, Simon Trowitzsch, Ambro Van Hoof
Student and Faculty Publications
Through its role in intron cleavage, tRNA splicing endonuclease (TSEN) plays a critical function in the maturation of intron-containing pre-tRNAs. The catalytic mechanism and core requirement for this process is conserved between archaea and eukaryotes, but for decades, it has been known that eukaryotic TSENs have evolved additional modes of RNA recognition, which have remained poorly understood. Recent research identified new roles for eukaryotic TSEN, including processing or degradation of additional RNA substrates, and determined the first structures of pre-tRNA-bound human TSEN complexes. These recent discoveries have changed our understanding of how the eukaryotic TSEN targets and recognizes substrates. Here, …
Molecular Mechanisms Of Snorna-Il-15 Crosstalk In Adipocyte Lipolysis And Nk Cell Rejuvenation, Yaohua Zhang, Zilong Zhao, Lisa A Huang, Yuan Liu, Jun Yao, Chengcao Sun, Yajuan Li, Zhao Zhang, Youqiong Ye, Fei Yuan, Tina K Nguyen, Nikhil Reddy Garlapati, Andrew Wu, Sergey D Egranov, Abigail S Caudle, Aysegul A Sahin, Bora Lim, Laura Beretta, George A Calin, Dihua Yu, Mien-Chie Hung, Michael A Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang
Molecular Mechanisms Of Snorna-Il-15 Crosstalk In Adipocyte Lipolysis And Nk Cell Rejuvenation, Yaohua Zhang, Zilong Zhao, Lisa A Huang, Yuan Liu, Jun Yao, Chengcao Sun, Yajuan Li, Zhao Zhang, Youqiong Ye, Fei Yuan, Tina K Nguyen, Nikhil Reddy Garlapati, Andrew Wu, Sergey D Egranov, Abigail S Caudle, Aysegul A Sahin, Bora Lim, Laura Beretta, George A Calin, Dihua Yu, Mien-Chie Hung, Michael A Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang
Student and Faculty Publications
Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced …
Starvation Sensing By Mycobacterial Rela/Spot Homologue Through Constitutive Surveillance Of Translation, Yunlong Li, Soneya Majumdar, Ryan Treen, Manjuli R. Sharma, Jamie Corro, Howard B. Gamper, Swati R. Manjari, Jerome Prusa, Nilesh K. Banavali, Christina L. Stallings, Ya-Ming Hou, Rajendra K. Agrawal, Anil K. Ojha
Starvation Sensing By Mycobacterial Rela/Spot Homologue Through Constitutive Surveillance Of Translation, Yunlong Li, Soneya Majumdar, Ryan Treen, Manjuli R. Sharma, Jamie Corro, Howard B. Gamper, Swati R. Manjari, Jerome Prusa, Nilesh K. Banavali, Christina L. Stallings, Ya-Ming Hou, Rajendra K. Agrawal, Anil K. Ojha
Department of Biochemistry and Molecular Biology Faculty Papers
The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homolog (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomes in vivo remains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner. This loss is also observed in nonstarved cells using mutations in Rsh that block its interaction with the ribosome, indicating that Rsh association with the ribosome is important for Rsh stability. The cryo-EM structure of the Rsh-bound 70S ribosome in …
Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco
Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco
Student and Faculty Publications
mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had …
Parp1 Associates With R-Loops To Promote Their Resolution And Genome Stability, Natalie Laspata, Parminder Kaur, Sofiane Yacine Mersaoui, Daniela Muoio, Zhiyan Silvia Liu, Maxwell Henry Bannister, Hai Dang Nguyen, Caroline Curry, John M. Pascal, Guy G. Poirier, Hong Wang, Jean-Yves Masson, Elise Fouquerel
Parp1 Associates With R-Loops To Promote Their Resolution And Genome Stability, Natalie Laspata, Parminder Kaur, Sofiane Yacine Mersaoui, Daniela Muoio, Zhiyan Silvia Liu, Maxwell Henry Bannister, Hai Dang Nguyen, Caroline Curry, John M. Pascal, Guy G. Poirier, Hong Wang, Jean-Yves Masson, Elise Fouquerel
Student Papers, Posters & Projects
PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation …
Semi-Quantitative Detection Of Pseudouridine Modifications And Type I/Ii I/Ii Hypermodifications In Human Mrnas Using Direct Long-Read Sequencing, Sepideh Tavakoli, Mohammad Nabizadeh, Amr Makhamreh, Howard Gamper, Caroline A Mccormick, Neda K Rezapour, Ya-Ming Hou, Meni Wanunu, Sara H Rouhanifard
Semi-Quantitative Detection Of Pseudouridine Modifications And Type I/Ii I/Ii Hypermodifications In Human Mrnas Using Direct Long-Read Sequencing, Sepideh Tavakoli, Mohammad Nabizadeh, Amr Makhamreh, Howard Gamper, Caroline A Mccormick, Neda K Rezapour, Ya-Ming Hou, Meni Wanunu, Sara H Rouhanifard
Department of Biochemistry and Molecular Biology Faculty Papers
Here, we develop and apply a semi-quantitative method for the high-confidence identification of pseudouridylated sites on mammalian mRNAs via direct long-read nanopore sequencing. A comparative analysis of a modification-free transcriptome reveals that the depth of coverage and specific k-mer sequences are critical parameters for accurate basecalling. By adjusting these parameters for high-confidence U-to-C basecalling errors, we identify many known sites of pseudouridylation and uncover previously unreported uridine-modified sites, many of which fall in k-mers that are known targets of pseudouridine synthases. Identified sites are validated using 1000-mer synthetic RNA controls bearing a single pseudouridine in the center position, demonstrating systematic …