Article
Oncology
Anthony B. B. El-Khoueiry, James Clarke, Tobias Neff, Tim Crossman, Nirav Ratia, Chetan Rathi, Paul Noto, Aarti Tarkar, Ignacio Garrido-Laguna, Emiliano Calvo, Jordi Rodon, Ben Tran, Peter J. J. O'Dwyer, Adam Cuker, Albiruni R. Abdul R. Razak
Summary: GSK3368715, a reversible inhibitor of type I protein methyltransferases, showed anticancer activity in preclinical studies. This Phase 1 study evaluated its safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced solid tumors. However, due to a higher-than-expected incidence of thromboembolic events, the study was terminated.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Shuangjie Liu, Zhuonan Liu, Chiyuan Piao, Zhe Zhang, Chuize Kong, Lei Yin, Xi Liu
Summary: The study reveals PRMT5 as a therapeutic target for bladder cancer and identifies FKA, extracted from the kava plant, as an inhibitor of PRMT5 for the treatment of bladder cancer.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Qin Wu, David Y. Nie, Wail Ba-alawi, YiShuai Ji, ZiWen Zhang, Jennifer Cruickshank, Jillian Haight, Felipe E. Ciamponi, Jocelyn Chen, Shili Duan, Yudao Shen, Jing Liu, Sajid A. Marhon, Parinaz Mehdipour, Magdalena M. Szewczyk, Nergiz Dogan-Artun, WenJun Chen, Lan Xin Zhang, Genevieve Deblois, Panagiotis Prinos, Katlin B. Massirer, Dalia Barsyte-Lovejoy, Jian Jin, Daniel D. De Carvalho, Benjamin Haibe-Kains, XiaoJia Wang, David W. Cescon, Mathieu Lupien, Cheryl H. Arrowsmith
Summary: This study identified an inhibitor called MS023 that has antitumor growth activity in triple-negative breast cancer (TNBC). Activation of interferon responses was found to be a functional biomarker and determinant of response in TNBC cell lines and human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Analytical
Zhen Liu, Keyun Wang, Mingliang Ye
Summary: In order to understand the function of protein arginine methyltransferases(PRMTs), it is crucial to identify their substrate proteins. However, this is challenging due to the dominance of stable and strong interacting proteins over weak and transient substrate proteins. In this study, a novel photoreactive probe-based strategy was developed to identify the substrate proteins of methyltransferases, specifically PRMT1. This strategy effectively distinguished substrate proteins from other interacting proteins and allowed the identification of highly confident substrate proteins. Importantly, it was discovered that hypomethylation of proteins is a prerequisite for efficient capturing of substrate proteins. This study describes the development of a robust chemical proteomic tool for profiling transient substrates and has broad biomedical applications.
ANALYTICAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Ayad A. Al-Hamashi, Dongxing Chen, Youchao Deng, Guangping Dong, Rong Huang
Summary: This study reported the design and synthesis of bisubstrate analogues for PRMTs, with compound AH237 showing potent and selective inhibition towards PRMT4 and PRMT5. Computational studies provided insights into the high potency and selectivity of AH237, offering a valuable strategy for developing inhibitors for PRMTs in the future.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Endocrinology & Metabolism
Seri Choi, Dahee Choi, Yun-Kyung Lee, Seung Hyun Ahn, Je Kyung Seong, Sung Wook Chi, Tae Jung Oh, Sung Hee Choi, Seung-Hoi Koo
Summary: PRMT1 plays a crucial role in maintaining metabolic balance in adipose tissues, with its depletion leading to increased lipid catabolism and adverse effects in conditions of high-fat diet or obesity, such as promotion of adipose tissue inflammation and ectopic accumulation of triglycerides.
Review
Medicine, Research & Experimental
Jiaoyang Ning, Liu Chen, Gang Xiao, Yu Zeng, Wen Shi, Guilong Tanzhu, Rongrong Zhou
Summary: PRMTs are involved in the prognosis and metastasis of tumors, and their regulation of molecular mechanisms affects tumor metastasis. Inhibiting arginine methylation can reduce tumor metastasis, and this field holds promise for clinical application.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Microbiology
Xiaohui Ju, Yanying Yu, Wenlin Ren, Lin Dong, Xianbin Meng, Haiteng Deng, Yuchen Nan, Qiang Ding
Summary: This study systematically analyzed the host factors in HEV replication complex using ORF1 trans-complementation system and HEV replicon. The PRMT5/WDR77 complex was found to have an inhibitory role in HEV infection among different HEV strains, but not in HCV and SARS-CoV-2 infection. The complex methylates the 458th arginine in HEV ORF1, which is responsible for HEV replication. The findings provide insights into HEV replication and viral-host interaction, and inform antiviral strategies against HEV infection.
Review
Biochemistry & Molecular Biology
Kai Zheng, Siyu Chen, Zhe Ren, Yifei Wang
Summary: PRMT-mediated arginine methylation is an important post-transcriptional modification that plays a crucial role in cellular processes and viral infections. Understanding the regulation of arginine methylation provides insights into the pathogenesis of viral diseases and opportunities for antiviral therapy.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Article
Oncology
Noelia Che, Kai-Yu Ng, Tin-Lok Wong, Man Tong, Phillis W. F. Kau, Lok-Hei Chan, Terence K. Lee, Michael S. Y. Huen, Jing-Ping Yun, Stephanie Ma
Summary: Autophagy plays a critical role in cancer cells such as hepatocellular carcinoma (HCC), and deficiency of the post-translational modification enzyme PRMT6 promotes autophagy induction in HCC under stress conditions. PRMT6 interacts with and methylates BAG5 to regulate HSC70 stability, influencing autophagy in HCC cells. Targeting BAG5 may be a promising strategy in HCC treatment to suppress autophagy and enhance sensitivity to sorafenib.
Article
Biochemistry & Molecular Biology
Joshua J. Hamey, Sinja Rakow, Caroline Bouchard, Johanna M. Senst, Peter Kolb, Uta-Maria Bauer, Marc R. Wilkins, Gene Hart-Smith
Summary: PRMT6 catalyzes the asymmetric dimethylation of arginines on substrate proteins, including histone H3, affecting gene regulation. This study systematically characterized PRMT6's substrate recognition motif, showing broad specificity and a preference for the RG motif. Despite efficient methylation at H3R2, PRMT6 tolerates various amino acid substitutions in the H3 peptide, with preference for positively charged and bulky residues near the target arginine.
Article
Parasitology
Gustavo Daniel Campagnaro, Lucas Bigolin Lorenzon, Mateus Augusto Rodrigues, Tania Paula Aquino Defina, Camila Figueiredo Pinzan, Tiago Rodrigues Ferreira, Angela Kaysel Cruz
Summary: Arginine methylation by PRMTs affects protein function, protein-protein interactions, cell metabolism, and gene expression control. Leishmania parasites express five PRMTs, and their imbalanced activity can impact parasite virulence. Overexpression of PRMT6 in Leishmania major impairs infection in mice, resulting in reduced parasite numbers in lymph nodes. Our findings suggest a significant role of LmjPRMT6-mediated arginine methylation in parasite adaptation to the mammalian host environment.
Review
Cell Biology
Britta Qualmann, Michael M. Kessels
Summary: The development and plasticity of neuronal arbors require tight control of actin filament assembly and dynamics, with arginine methylation playing a crucial role in regulating these processes.
Review
Biochemistry & Molecular Biology
Young-Su Yi
Summary: Inflammasome, activated in response to infection and damage, triggers inflammatory responses, while methylation, a critical biological process, modulates gene expression. The functional relationship between inflammasome regulation and methylation may play a key role in inflammatory responses and disease development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Genetics & Heredity
Justin Chan, Amarjeet Kumar, Hidetoshi Kono
Summary: This review focuses on the role of RNA polymerase II (RNAPII) in establishing specific distributions of histone posttranslational modifications (PTMs) throughout the chromatin. Two major mechanisms are discussed: the change in phosphorylation patterns of RNAPII links to the elongation rate, recruiting specific histone PTM enzymes/activators to the nucleosome and determining the location of modifications; multiple rounds of binding and catalysis determine the methylation level and the modification state.
TRENDS IN GENETICS
(2022)
Article
Multidisciplinary Sciences
Yichen Zhong, Bishnu P. Paudel, Daniel P. Ryan, Jason K. K. Low, Charlotte Franck, Karishma Patel, Max J. Bedward, Mario Torrado, Richard J. Payne, Antoine M. van Oijen, Joel P. Mackay
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Karishma Patel, Louise J. Walport, James L. Walshe, Paul D. Solomon, Jason K. K. Low, Daniel H. Tran, Kevork S. Mouradian, Ana P. G. Silva, Lorna Wilkinson-White, Alexander Norman, Charlotte Franck, Jacqueline M. Matthews, J. Mitchell Guss, Richard J. Payne, Toby Passioura, Hiroaki Suga, Joel P. Mackay
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Biochemistry & Molecular Biology
Cecy R. Xi, Arianna Di Fazio, Naveed Ahmed Nadvi, Karishma Patel, Michelle Sui Wen Xiang, Hui Emma Zhang, Chandrika Deshpande, Jason K. K. Low, Xiaonan Trixie Wang, Yiqian Chen, Christopher L. D. McMillan, Ariel Isaacs, Brenna Osborne, Ana Julia Vieira de Ribeiro, Geoffrey W. McCaughan, Joel P. Mackay, W. Bret Church, Mark D. Gorrell
Article
Biochemistry & Molecular Biology
Karishma Patel, Paul D. Solomon, James L. Walshe, Jason K. K. Low, Joel P. Mackay
Summary: Chemical modifications of histone tails influence genome accessibility and transcriptional state of eukaryotic cells. The study reveals a physical interaction between the BET family BD proteins and the essential histone variant H2A.Z, mediated by lysine acetylation. This interaction suggests a mechanism for the function of H2A.Z through interactions with chromatin readers.
Article
Cell Biology
Jason K. K. Low, Ana P. G. Silva, Mehdi Sharifi Tabar, Mario Torrado, Sarah R. Webb, Benjamin L. Parker, Maryam Sana, Callum Smits, Jason W. Schmidberger, Lou Brillault, Matthew J. Jackman, David C. Williams, Gerd A. Blobel, Sandra B. Hake, Nicholas E. Shepherd, Michael J. Landsberg, Joel P. Mackay
Article
Biochemistry & Molecular Biology
Karishma Patel, Paul D. Solomon, James L. Walshe, Daniel J. Ford, Lorna Wilkinson-White, Richard J. Payne, Jason K. K. Low, Joel P. Mackay
Summary: The study investigates the interactions between BET and transcription factors, showing acetylation-dependent interactions between motifs in E2F1 and MyoD1 and the bromodomains of BRD2, BRD3, and BRD4. Structural mapping confirms a conserved binding mode and suggests a physical link between diacetylated motifs in E2F1 and MyoD1 and BET-family proteins.
Article
Biochemistry & Molecular Biology
Mehdi Sharifi Tabar, Caroline Giardina, Yue Feng, Habib Francis, Hakimeh Moghaddas Sani, Jason K. K. Low, Joel P. Mackay, Charles G. Bailey, John E. J. Rasko
Summary: This study provides insights into the protein-protein interaction network of the MGCC module and its role in gene regulation, particularly shedding light on the mechanisms underlying paralogue-specific functions and specificity.
Article
Chemistry, Multidisciplinary
Alexander Norman, Charlotte Franck, Mary Christie, Paige M. E. Hawkins, Karishma Patel, Anneliese S. Ashhurst, Anupriya Aggarwal, Jason K. K. Low, Rezwan Siddiquee, Caroline L. Ashley, Megan Steain, James A. Triccas, Stuart Turville, Joel P. Mackay, Toby Passioura, Richard J. Payne
Summary: The COVID-19 pandemic caused severe morbidity, mortality, and disruption globally. Research has identified cyclic peptide ligands with high affinity to the SARS-CoV-2 spike protein receptor binding domain, which may have potential future use as diagnostic reagents.
ACS CENTRAL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Marek Jindra, William J. McKinstry, Thomas Nebl, Lenka Bittova, Bin Ren, Jan Shaw, Tram Phan, Louis Lu, Jason K. K. Low, Joel P. Mackay, Lindsay G. Sparrow, George O. Lovrecz, Ronald J. Hill
Summary: Juvenile hormone (JH) plays important roles in insect reproduction, development, and physiology primarily by interacting with JH receptor (JHR) at the gene-regulatory level. This study presents a method for high-yield expression and purification of JHR complexes from two insect species and provides initial insights into JHR structure and function.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Charlotte Hodson, Jason K. K. Low, Sylvie van Twest, Samuel E. Jones, Paolo Swuec, Vincent Murphy, Kaima Tsukada, Matthew Fawkes, Rohan Bythell-Douglas, Adelina Davies, Jessica K. Holien, Julienne J. O'Rourke, Benjamin L. Parker, Astrid Glaser, Michael W. Parker, Joel P. Mackay, Andrew N. Blackford, Alessandro Costa, Andrew J. Deans
Summary: The RecQ-like helicase BLM cooperates with topoisomerase IIIa to dissolve double Holliday junctions in homologous recombination. Mutations in the Bloom syndrome complex can cause genome instability and cancer susceptibility, including breast cancer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Immunology
Claudio Counoupas, Matt D. Johansen, Alberto O. Stella, Duc H. Nguyen, Angela L. Ferguson, Anupriya Aggarwal, Nayan D. Bhattacharyya, Alice Grey, Owen Hutchings, Karishma Patel, Rezwan Siddiquee, Erica L. Stewart, Carl G. Feng, Nicole G. Hansbro, Umaimainthan Palendira, Megan C. Steain, Bernadette M. Saunders, Jason K. K. Low, Joel P. Mackay, Anthony D. Kelleher, Warwick J. Britton, Stuart G. Turville, Philip M. Hansbro, James A. Triccas
Summary: This study demonstrates the potential of a BCG-based vaccine to provide protection against major SARS-CoV-2 variants by inducing potent virus-specific immune responses. Pre-treatment with BCG:CoVac followed by a heterologous vaccine boosts SARS-CoV-2-specific antibody responses effectively neutralizing key variants.
Article
Biochemistry & Molecular Biology
Shreyas Arvindekar, Matthew J. Jackman, Jason K. K. Low, Michael J. Landsberg, Joel P. Mackay, Shruthi Viswanath
Summary: Using an integrative structure determination approach, researchers have revealed the molecular architecture of nucleosome deacetylase (NuDe) sub-complexes within the nucleosome remodeling and deacetylase (NuRD) complex. The study identified previously unrecognized subunit interfaces and located regions of unknown structure, resulting in the most complete and robustly cross-validated structural characterization of these NuRD sub-complexes to date.
Article
Multidisciplinary Sciences
Yichen Zhong, Hakimeh Moghaddas Sani, Bishnu P. Paudel, Jason K. K. Low, Ana P. G. Silva, Stefan Mueller, Chandrika Deshpande, Santosh Panjikar, Xavier J. Reid, Max J. Bedward, Antoine M. van Oijen, Joel P. Mackay
Summary: CHD4 is an essential ATP-dependent translocase that alters chromatin accessibility by repositioning histone octamers. The N-terminal intrinsically disordered region (IDR) promotes remodelling integrity, while the C-terminal region harbours an auto-inhibitory region that is relieved by binding to substrate DNA.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Tara K. Bartolec, Xabier Vazquez-Campos, Alexander Norman, Clement Luong, Marcus Johnson, Richard J. Payne, Marc R. Wilkins, Joel P. Mackay, Jason K. K. Low
Summary: Significant advances in cryoelectron microscopy have expanded our ability to create structural models of proteins and protein complexes. Cross-linking mass spectrometry (XL-MS) is demonstrated to be a powerful tool for high-throughput experimental assessment of protein structures and interactions. The combination of XL-MS data with AlphaFold2 predictions offers opportunities to explore the structural proteome and interactome in depth.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Chemistry, Multidisciplinary
Louise J. Walport, Jason K. K. Low, Jacqueline M. Matthews, Joel P. Mackay
Summary: This review provides an overview of techniques used to identify protein partners, assess stoichiometry and binding affinity, and determine low-resolution models for complexes.
CHEMICAL SOCIETY REVIEWS
(2021)