Article
Biochemistry & Molecular Biology
Alec C. Gleason, Ghanashyam Ghadge, Yoshifumi Sonobe, Raymond P. Roos
Summary: Ribosome profiling and mass spectroscopy have identified noncanonical translation initiation codons (TICs) that translate oncogenic proteins. These TICs have flanking nucleotides closely matching the Kozak sequence, and cancer-associated genes have longer 5'UTRs, increasing the likelihood of ribosome binding to noncanonical TICs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Kazuya Ichihara, Akinobu Matsumoto, Hiroshi Nishida, Yuki Kito, Hideyuki Shimizu, Yuichi Shichino, Shintaro Iwasaki, Koshi Imami, Yasushi Ishihama, Keiichi Nakayama
Summary: TISCA is a new method for accurately identifying translation initiation sites, proving to be more reliable than existing tools and identifying a substantial number of near-cognate codons in Kozak-like sequence contexts.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Lorenzo Calviello, Srivats Venkataramanan, Karol J. Rogowski, Emanuel Wyler, Kevin Wilkins, Malvika Tejura, Bao Thai, Jacek Krol, Witold Filipowicz, Markus Landthaler, Stephen N. Floor
Summary: DDX3 is an RNA chaperone that regulates translation by affecting a subset of mRNAs. The specific set of mRNAs regulated by DDX3 and its relationship with activity are still unknown. This study defines the subset of the transcriptome responsive to DDX3 inhibition, with implications for basic biology and disease states involving altered DDX3.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Paul Powell, Usha Bhardwaj, Dixie Goss
Summary: This study identifies secondary structures that selectively interact with eIF3 and explores its role in translation initiation of BYDV. The findings propose a new model for BYDV translation initiation and expand the known functionality of eIF3.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemical Research Methods
Loveday E. Lewin, Kate G. Daniels, Laurence D. Hurst
Summary: It has been found that initiation optimality codons, which are synonymous codons that promote efficient translation initiation, are not commonly used in native genes encoding highly abundant proteins. However, initiation optimality scores derived from transgene experiments may be relevant for in silico transgene design for a wide range of bacteria.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alexandra Filatova, Ivan Reveguk, Maria Piatkova, Daria Bessonova, Olga Kuziakova, Victoria Demakova, Alexander Romanishin, Veniamin Fishman, Yerzhan Imanmalik, Nikolay Chekanov, Rostislav Skitchenko, Yury Barbitoff, Olga Kardymon, Mikhail Skoblov
Summary: An increasing number of studies highlight the significance of non-coding variants in hereditary diseases. However, the interpretation of such variants in clinical genetic testing remains challenging due to limited knowledge of their pathogenicity mechanisms. This study manually annotated upstream translation initiation sites (TISs) in human disease-associated genes and identified numerous TISs related to upstream open reading frames (uORFs). A machine-learning algorithm was also developed to predict TISs in other human genes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Zheng Bin Randolph Quek, Jia Jin Marc Chang, Yin Cheong Aden Ip, Yong Kit Samuel Chan, Danwei Huang
Summary: The mitochondrial genetic code in invertebrates is more diverse than the standard genetic code, with the identification of new initiation codons in sea stars. Gene order among asteroids, echinoids, and holothuroids is remarkably conserved, with few changes over 500 million years of echinoderm evolution.
MOLECULAR BIOLOGY AND EVOLUTION
(2021)
Article
Biochemistry & Molecular Biology
John H. Kim, Matthew S. Modena, Enisha Sehgal, Annie Courney, Celine W. Neudorf, Joshua A. Arribere
Summary: NMD is a mechanism that protects cells from the effects of truncated proteins, and previous studies have identified a novel NMD intermediate where ribosomes stall on cleaved stop codons. Our research shows that this intermediate is the result of mRNA cleavage by the endonuclease SMG-6.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Virology
Ghobad Babaei, Amir Massah, Mina Koohi Habibi
Summary: Translation circularization of RNA mediated by translation factors and RNA elements in 5' and 3' UTRs is crucial for translation control. The study on EMDV genes reveals the significance of both 5' and 3' UTRs in translation, with potential alternative mechanisms and critical role of polyadenylation signal sequence in translation.
Article
Multidisciplinary Sciences
Jicong Cao, Eva Maria Novoa, Zhizhuo Zhang, William C. W. Chen, Dianbo Liu, Gigi C. G. Choi, Alan S. L. Wong, Claudia Wehrspaun, Manolis Kellis, Timothy K. Lu
Summary: By using a high-throughput screening approach on 5'UTR libraries, this study identified three synthetic 5'UTRs that outperformed commonly used non-viral gene therapy plasmids in expressing protein payloads. This finding has important implications for engineered cell and gene therapies.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Nicholas K. Clark, Meghan T. Harris, William B. Dahl, Zachary Knotts, Michael T. Marr II
Summary: IRES-mediated translation initiation requires a different set of factors compared to canonical cap-dependent translation. Cellular IRES mechanisms may resemble viral type III IRESes, allowing them to function with limited initiation factors under stress conditions.
MOLECULAR AND CELLULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
L. Wang, R. Li, X. Lai, X. Zhang, H. Chen, W. Zhao
Summary: Siglec-15, an immune suppressor with broad upregulation on various cancer types, has become a potential target for cancer immunotherapy. This study reveals that the 3’UTR of SIGLEC15 mRNA inhibits gene expression by accelerating mRNA degradation, while the 5’UTR represses gene expression by inhibiting translation. These findings provide insights into the molecular mechanism underlying the regulation of SIGLEC15 expression.
Article
Multidisciplinary Sciences
Yifei Gu, Yuanhui Mao, Longfei Jia, Leiming Dong, Shu-Bing Qian
Summary: The fidelity of start codon recognition by ribosomes is crucial for protein synthesis. Recent studies suggest that ribosomes can select upstream AUG codons via backsliding on the mRNA, with the RNA helicase eIF4A playing a key role in this process.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Qian Liang, Yaqi Jin, Shiwen Xu, Junzhi Zhou, Jian Mao, Xiaohe Ma, Miao Wang, Yu-Sheng Cong
Summary: This study reveals the functional role of human UFSP1 as an active UFM1-specific protease, contributing to our understanding of the UFMylation/de-UFMylation process.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Plant Sciences
Haruka Higashi, Yoshinobu Kato, Tomoya Fujita, Shintaro Iwasaki, Masayuki Nakamura, Yoshiki Nishimura, Mizuki Takenaka, Toshiharu Shikanai
Summary: The study reveals that PGR3 not only promotes translation of petL but also of ndhG by binding to their 5' UTRs, counteracting the inhibitory effects of RNA secondary structures to facilitate protein synthesis. The 3-dimensional structure prediction of PGR3 indicates the importance of the 26th PPR motif in target RNA binding.
PLANT AND CELL PHYSIOLOGY
(2021)
Article
Multidisciplinary Sciences
Jeffrey J. Quinn, Matthew G. Jones, Ross A. Okimoto, Shigeki Nanjo, Michelle M. Chan, Nir Yosef, Trever G. Bivona, Jonathan S. Weissman
Summary: This study used a Cas9-based lineage tracer to track the development and metastasis of lung cancer cells in a mouse model over months, revealing heterogeneity in metastatic capacity and genetic differences that drive invasiveness. The study also uncovered some genes driving metastasis and an unexpected suppressive role of KRT17 in metastasis.
Article
Oncology
Yuan-Hung Lo, Kevin S. Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter D. Sobba, Kasper Karlsson, Sunny J. Jones, Teri A. Longacre, Amanda T. Mah, Bahar Tercan, Alexandra Sockell, Hang Xu, Jose A. Seoane, Jin Chen, Ilya Shmulevich, Jonathan S. Weissman, Christina Curtis, Andrea Califano, Haian Fu, Gerald R. Crabtree, Calvin J. Kuo
Summary: Mutations in ARID1A are common in human cancer, but the oncogenic consequences of these mutations remain unclear. Using CRISPR/Cas9, researchers induced dysplasia, tumorigenicity, and mucinous differentiation in human gastric organoids, providing insights into the pathways affected by ARID1A mutation. Further analysis showed vulnerability of ARID1A-deficient organoids to inhibition of BIRC5/survivin, highlighting this pathway as crucial for early-stage gastric tumorigenesis.
Article
Cell Biology
Kuanqing Liu, Daniel A. Santos, Jeffrey A. Hussmann, Yun Wang, Benjamin M. Sutter, Jonathan S. Weissman, Benjamin P. Tu
Summary: N-6-methyladenosine (m(6)A) is a conserved ribonucleoside modification that regulates RNA metabolism. This study found that tandem adenosines at the 3' end of 18S rRNA are also methylated, with significantly increased levels in response to sulfur starvation. Ribosomes with m(6)A were shown to have distinct translation preferences for sulfur metabolism genes.
Article
Biochemistry & Molecular Biology
James K. Nunez, Jin Chen, Greg C. Pommier, J. Zachery Cogan, Joseph M. Replogle, Carmen Adriaens, Gokul N. Ramadoss, Quanming Shi, King L. Hung, Avi J. Samelson, Angela N. Pogson, James Y. S. Kim, Amanda Chung, Manuel D. Leonetti, Howard Y. Chang, Martin Kampmann, Bradley E. Bernstein, Volker Hovestadt, Luke A. Gilbert, Jonathan S. Weissman
Summary: CRISPRoff is a programmable epigenetic memory writer that can heritably alter gene expression by initiating specific DNA methylation and gene repression. The tool utilizes a single dead Cas9 fusion protein to establish these modifications, which are maintained through cell division and differentiation processes. By pairing CRISPRoff with genome-wide screens and analysis of chromatin marks, rules for heritable gene silencing can be established, with the tool capable of targeting a wide range of genes beyond canonical CpG islands.
Article
Biology
Marco Jost, Amy N. Jacobson, Jeffrey A. Hussmann, Giana Cirolia, Michael A. Fischbach, Jonathan S. Weissman
Summary: A CRISPR-Cas9 genome editing method for human monocyte-derived DCs was developed, enabling knockouts with high efficiency and genetic screens. Donor-specific responses to lipopolysaccharides were revealed, emphasizing the importance of assessing immune phenotypes and identifying candidate genes that control specificity. This method has the potential to pinpoint determinants of inter-individual variation in immunity.
Article
Biochemistry & Molecular Biology
Xiaojie Qiu, Yan Zhang, Jorge D. Martin-Rufino, Chen Weng, Shayan Hosseinzadeh, Dian Yang, Angela N. Pogson, Marco Y. Hein, Kyung Hoi (Joseph) Min, Li Wang, Emanuelle Grody, Matthew J. Shurtleff, Ruoshi Yuan, Song Xu, Yian Ma, Joseph M. Replogle, Eric S. Lander, Spyros Darmanis, Ivet Bahar, Vijay G. Sankaran, Jianhua Xing, Jonathan S. Weissman
Summary: This article introduces an analytical framework called dynamo, which combines single-cell RNA-seq, RNA velocity, and metabolic labeling to reveal cellular states and transitions. It can predict cell fates and perturbation outcomes, and overcome the limitations of conventional splicing-based RNA velocity analyses.
Article
Biotechnology & Applied Microbiology
Marco Y. Hein, Jonathan S. Weissman
Summary: Understanding the roles of viral and host factors in human cytomegalovirus infection was explored using CRISPR interference and nuclease screening. The study revealed how perturbations of critical host and viral factors can alter the progression and timing of infection. Results showed that perturbing host factors can impact the stage of infection, while perturbation of viral factors can lead to distinct infection trajectories.
NATURE BIOTECHNOLOGY
(2022)
Article
Cell Biology
Avi J. Samelson, Quang Dinh Tran, Remy Robinot, Lucia Carrau, Veronica V. Rezelj, Alice Mac Kain, Merissa Chen, Gokul N. Ramadoss, Xiaoyan Guo, Shion A. Lim, Irene Lui, James K. Nunez, Sarah J. Rockwood, Jianhui Wang, Na Liu, Jared Carlson-Stevermer, Jennifer Oki, Travis Maures, Kevin Holden, Jonathan S. Weissman, James A. Wells, Bruce R. Conklin, Benjamin R. TenOever, Lisa A. Chakrabarti, Marco Vignuzzi, Ruilin Tian, Martin Kampmann
Summary: The protein BRD2 is found to be crucial for ACE2 transcription and SARS-CoV-2 infection in human lung epithelial cells and cardiomyocytes. BRD2 inhibitors can effectively block endogenous ACE2 expression and viral infection in human cells, including nasal epithelial cells. Furthermore, inhibiting BRD2 with a drug called ABBV-744 can suppress SARS-CoV-2 replication in Syrian hamsters. BRD2 also controls the transcription of several other genes induced by SARS-CoV-2 infection, including the interferon response, which regulates the antiviral response.
NATURE CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Noa Dahan, Yury S. Bykov, Elizabeth A. Boydston, Amir Fadel, Zohar Gazi, Hodaya Hochberg-Laufer, James Martenson, Vlad Denic, Yaron Shav-Tal, Jonathan S. Weissman, Naama Aviram, Einat Zalckvar, Maya Schuldiner
Summary: This study discovered that translation of specific peroxisomal membrane proteins (PMPs) occurs on the surface of peroxisomes in yeast, similar to chloroplasts, mitochondria, and the endoplasmic reticulum. This localized translation process ensures the correct insertion of hydrophobic proteins into the peroxisomal membrane. Proper targeting of PMP transcripts to peroxisomes is crucial for cellular and peroxisomal function, highlighting the importance of localized translation in cellular physiology.
Article
Biochemistry & Molecular Biology
Dian Yang, Matthew G. Jones, Santiago Naranjo, William M. Rideout III, Kyung Hoi (Joseph) Min, Raymond Ho, Wei Wu, Joseph M. Replogle, Jennifer L. Page, Jeffrey J. Quinn, Felix Horns, Xiaojie Qiu, Michael Z. Chen, William A. Freed-Pastor, Christopher S. McGinnis, David M. Patterson, Zev J. Gartner, Eric D. Chow, Trever G. Bivona, Michelle M. Chan, Nir Yosef, Tyler Jacks, Jonathan S. Weissman
Summary: Tumor evolution is driven by progressive genetic and epigenetic alterations, enabling unrestricted growth and expansion. This study provides insights into the hierarchical nature of tumor evolution through tracking phylogenetic relationships between cancer cells, allowing for in-depth studies of tumor progression.
Article
Multidisciplinary Sciences
Nathan H. Cho, Keith C. Cheveralls, Andreas-David Brunner, Kibeom Kim, Andre C. Michaelis, Preethi Raghavan, Hirofumi Kobayashi, Laura Savy, Jason Y. Li, Hera Canaj, James Y. S. Kim, Edna M. Stewart, Christian Gnann, Frank McCarthy, Joana P. Cabrera, Rachel M. Brunetti, Bryant B. Chhun, Greg Dingle, Marco Y. Hein, Bo Huang, Shalin B. Mehta, Jonathan S. Weissman, Rafael Gomez-Sjoberg, Daniel N. Itzhak, Loic A. Royer, Matthias Mann, Manuel D. Leonetti
Summary: This article introduces a method that uses various techniques to systematically map the localization and interactions of human proteins, and discovers the rich functional information contained in protein localization patterns.
Review
Cell Biology
Bradley W. Wright, Zixin Yi, Jonathan S. Weissman, Jin Chen
Summary: Omics-based technologies have revealed the existence of unannotated open reading frames (ORFs) in genomes, which have the potential to encode novel functional proteins or have regulatory roles. However, there is still limited understanding of these noncanonical ORFs in the scientific community, despite the few that have been studied and shown to play important roles in biological processes.
TRENDS IN CELL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Joseph M. Replogle, Reuben A. Saunders, Angela N. Pogson, Jeffrey A. Hussmann, Alexander Lenail, Alina Guna, Lauren Mascibroda, Eric J. Wagner, Karen Adelman, Gila Lithwick-Yanai, Nika Iremadze, Florian Oberstrass, Doron Lipson, Jessica L. Bonnar, Marco Jost, Thomas M. Norman, Jonathan S. Weissman
Summary: Understanding the relationships between genotypes and phenotypes is a central goal in genetics. This study demonstrates the use of a high-content phenotypic screening technique, Perturb-seq, to analyze over 2.5 million human cells at a genome-wide scale. Through this analysis, new gene functions and complex cellular phenomena were revealed.
Article
Biotechnology & Applied Microbiology
Fulong Yu, Liam D. Cato, Chen Weng, L. Alexander Liggett, Soyoung Jeon, Keren Xu, Charleston W. K. Chiang, Joseph L. Wiemels, Jonathan S. Weissman, Adam J. de Smith, Vijay G. Sankaran
Summary: Genome-wide association studies combined with single-cell genomic atlases can reveal the mechanisms of disease-causal genetic variations. However, sparse and noisy single-cell epigenomic data analysis often hinders the identification of disease-relevant cell types. To overcome this, the SCAVENGE algorithm uses network propagation to map causal variants to their relevant cellular context at a single-cell resolution, successfully identifying key biological mechanisms in various blood traits and diseases.
NATURE BIOTECHNOLOGY
(2022)
Article
Multidisciplinary Sciences
Christoph Bock, Paul Datlinger, Florence Chardon, Matthew A. Coelho, Matthew B. Dong, Keith A. Lawson, Tian Lu, Laetitia Maroc, Thomas M. Norman, Bicna Song, Geoff Stanley, Sidi Chen, Mathew Garnett, Wei Li, Jason Moffat, Lei S. Qi, Rebecca S. Shapiro, Jay Shendure, Jonathan S. Weissman, Xiaowei Zhuang
Summary: CRISPR screens are a powerful tool for unbiased investigation of gene functions in various applications and species. By introducing genetically encoded perturbations into cell pools, these screens allow the evaluation of gene effects under biological challenges. High-content read-outs and dedicated software tools enhance the analysis and reproducibility of the results, making it a flexible and reliable method for biological discovery and drug development.
NATURE REVIEWS METHODS PRIMERS
(2022)