Article
Biochemistry & Molecular Biology
Mirko M. Maksimainen, Sudarshan Murthy, Sven T. Sowa, Albert Galera-Prat, Elena Rolina, Juha P. Heiskanen, Lari Lehtio
Summary: By modifying the structure of inhibitor molecules, the selectivity was successfully shifted from poly-ADP-ribosyltransferases to mono-ADP-ribosyltransferases, and the binding modes of analogs were experimentally verified. The study demonstrates a method to differentiate compound selectivity between mono- and poly-ribosyltransferases in the human ARTD family.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Daniel J. Sanderson, Kelsie M. Rodriguez, Daniel S. Bejan, Ninni E. Olafsen, Inga D. Bohn, Ana Kojic, Sunil Sundalam, Ivan R. Siordia, Anna K. Duell, Nancy Deng, Carsten Schultz, Denis M. Grant, Jason Matthews, Michael S. Cohen
Summary: PARP7 is a key negative regulator of cytosolic NA-sensors of the innate immune system. Through rational design, a pan-PARP inhibitor was converted into a potent selective PARP7 inhibitor. Treatment with the inhibitor and NA-sensor ligands synergistically induced expression of type I interferon. The results also showed that the inhibitor increased PARP7 protein levels and highlighted the importance of structurally distinct chemical probes for the same target.
CELL CHEMICAL BIOLOGY
(2023)
Article
Biology
Lavanya H. Palavalli Parsons, Sridevi Challa, Bryan A. Gibson, Tulip Nandu, MiKayla S. Stokes, Dan Huang, Jayanthi S. Lea, W. Lee Kraus
Summary: PARP-7, a mono(ADP-ribosyl) transferase, plays a role in ovarian cancer cells by influencing cell growth and migration. Through MARylation of alpha-tubulin, it promotes microtubule instability to regulate cell growth and motility, with implications in cancer-related cellular phenotypes.
Editorial Material
Biochemistry & Molecular Biology
Michael S. Cohen
Summary: ADP-ribosylation is a crucial post-translational modification, involving MAR and PAR. Researchers have identified distinct MAR and PAR readers using a chemical biology approach.
Article
Chemistry, Multidisciplinary
Qiang Liu, Gunnar Knobloch, Jim Voorneveld, Nico J. Meeuwenoord, Herman S. Overkleeft, Gijsbert A. van Der Marel, Andreas G. Ladurner, Dmitri Filippov
Summary: The translation discusses the significance of ADP-ribosylation and the chemical synthesis of linear ADP-ribose oligomers, as well as their affinity for ALC1. The study reveals the length-dependent binding manner of ADPr oligomers to ALC1, illustrating how the activity of this molecular machine is controlled by PAR.
Article
Chemistry, Medicinal
Maria Giulia Nizi, Mirko M. Maksimainen, Lari Lehtio, Oriana Tabarrini
Summary: This article presents recent advances in the understanding of the functions of mono-ADP-ribosylating PARP enzymes and their potential applications in treating diseases. By combining structural biology and medicinal chemistry, researchers have successfully designed potent small molecule inhibitors. The article focuses on a specific class of inhibitors with a specific motif and analyzes the available crystal structures to develop a pharmacophore model for designing new and more specific inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Maria Giulia Nizi, Mirko M. Maksimainen, Lari Lehtio, Oriana Tabarrini
Summary: Major advances have been made in defining functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), opening up potential applications for treating diseases. The combination of structural biology and medicinal chemistry has led to the development of potent small molecule inhibitors that bind to the catalytic domain. Most of these inhibitors are still in the early stages, but some have shown promising profiles as chemical tools. A compound targeting PARP7 has even progressed to clinical trials.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Cell Biology
Ann-Katrin Hopp, Michael O. Hottiger
Summary: ADP-ribosylation is a NAD(+)-dependent post-translational modification that can be found on proteins and nucleic acids, with poly-ADP-ribosylation being extensively studied compared to mono-ADP-ribosylation. Recent technological advances have enhanced our understanding of how intracellular NAD dynamics regulate ADP-ribosylation and how mono-ADP-ribosylation integrates into various cellular processes.
Review
Cell Biology
Yujie Gan, Huanhuan Sha, Renrui Zou, Miao Xu, Yuan Zhang, Jifeng Feng, Jianzhong Wu
Summary: This review provides an update on methodological advances in the study of ADP-ribosylation and discusses the function and therapeutic potential of mono-ADP-ribosylation in cancer.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Virology
Yousef M. O. Alhammad, Maithri M. Kashipathy, Anuradha Roy, Jean-Philippe Gagne, Peter McDonald, Philip Gao, Louis Nonfoux, Kevin P. Battaile, David K. Johnson, Erik D. Holmstrom, Guy G. Poirier, Scott Lovell, Anthony R. Fehr
Summary: The Mac1 proteins in SARS-CoV-2 and other CoVs are MAR-hydrolases with similar functions, suggesting compounds targeting these proteins may have broad anti-CoV activity. Understanding the biochemistry and enzyme activity of these proteins is critical for developing novel therapeutic strategies against COVID-19.
JOURNAL OF VIROLOGY
(2021)
Article
Chemistry, Multidisciplinary
Jim Voorneveld, Johannes Gregor Matthias Rack, Luke van Gijlswijk, Nico J. Meeuwenoord, Qiang Liu, Herman S. Overkleeft, Gijsbert A. van Der Marel, Ivan Ahel, Dmitri V. Filippov
Summary: ADP-ribosylation is crucial in DNA-repair, immunity, and other cellular processes with serine being the main acceptor. A new solid-phase strategy for synthesizing Ser-, Thr-, and Cys-MARylated peptides has been described. ADP-ribosylated cysteine is a stable bioisostere for ADP-ribosylated serine and the protein SpyMacroD from Streptococcus pyogenes acts as a Cys-(ADP-ribosyl) hydrolase.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Cell Biology
Marit Rasmussen, Susanna Tan, Venkata S. Somisetty, David Hutin, Ninni Elise Olafsen, Anders Moen, Jan H. Anonsen, Denis M. Grant, Jason Matthews
Summary: PARP7 is a mono-ADP-ribosyltransferase involved in various cellular processes, including regulation of estrogen receptor alpha signaling. PARP7 mono-ADP-ribosylates estrogen receptor alpha, potentially playing a significant role in estrogen receptor positive breast cancer.
Article
Biochemistry & Molecular Biology
Johannes Rudolph, Karolin Luger
Summary: The auxiliary factor HPF1 redirects the enzymatic activity of PARP1, altering the PAR modification of proteins and affecting DNA repair in cells.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Maria Laura Kevorkian, Salome C. Vilchez Larrea, Silvia H. Fernandez Villamil
Summary: This study identifies the nuclear localization of TcPARP and its enrichment in the nucleolus of Trypanosoma cruzi. The study also reveals the presence of TcPARP in a thread-like structure connecting two dividing nuclei, and the detection of ADP-ribose polymers in this structure during mitosis. These findings shed light on new potential functions of TcPARP inside the nucleus and contribute to our understanding of its role in trypanosomatids beyond the well-described DNA damage response.
Article
Virology
Lakshminarayan M. Iyer, A. Maxwell Burroughs, Vivek Anantharaman, L. Aravind
Summary: This study provides a comprehensive investigation of the NAD(+)-ADPr networks in virus-host conflicts and reveals their importance in viral replication and evasion. The findings suggest that these networks have been widely exploited by RNA and DNA viruses, and there is a selection for genes encoding NAD(+)-ADPr-utilizing domains across the viral world.
Article
Chemistry, Physical
Linqiong Qiu, Cong Shen, Jianing Song, Yingkai Zhang, John Z. H. Zhang
Article
Chemistry, Medicinal
Hong Mu, Yingkai Zhang, Nicholas E. Geacintov, Suse Broyde
CHEMICAL RESEARCH IN TOXICOLOGY
(2018)
Article
Multidisciplinary Sciences
Jinping Lei, Gang Sheng, Peter Pak-Hang Cheung, Shenglong Wang, Yu Li, Xin Gao, Yingkai Zhang, Yanli Wang, Xuhui Huang
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Biochemistry & Molecular Biology
Kangshuai Li, Xuben Hou, Ruirui Li, Wenxiang Bi, Fan Yang, Xu Chen, Peng Xiao, Tiantian Liu, Tiange Lu, Yuan Zhou, Zhaomei Tian, Yuemao Shen, Yingkai Zhang, Jiangyun Wang, Hao Fang, Jinpeng Sun, Xiao Yu
JOURNAL OF BIOLOGICAL CHEMISTRY
(2019)
Article
Chemistry, Physical
Jianing Lu, Cheng Wang, Yingkai Zhang
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2019)
Article
Biochemistry & Molecular Biology
William M. Marsiglia, Joseph Katigbak, Sijin Zheng, Moosa Mohammadi, Yingkai Zhang, Nathaniel J. Traasethl
Article
Biochemistry & Molecular Biology
Lauren T. Que, Marie E. Morrow, Cynthia Wolberger
Article
Biology
Evan J. Worden, Xiangbin Zhang, Cynthia Wolberger
Review
Biochemistry & Molecular Biology
Cynthia Wolberger
Summary: Over the past four decades, significant progress has been made in our understanding of the structural basis of gene regulation, thanks to technological advances in protein expression, nucleic acid synthesis, and structural biology. This review focuses on insights gained from structural studies of protein-DNA complexes and the role the Protein Data Bank has played in driving this research. From X-ray crystal structures to recent cryo-EM structures, the highlights of the field are covered, detailing the study of transcription factors binding to nucleosomal DNA.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Sanim Rahman, Niklas A. Hoffmann, Evan J. Worden, Marissa L. Smith, Kevin E. W. Namitz, Bruce A. Knutson, Michael S. Cosgrove, Cynthia Wolberger
Summary: This study determines the structure of the MLL1-WRAD complex bound to ubiquitinated nucleosomes using an integrated approach. The structure reveals the conformation of Ash2L's intrinsically disordered region, SPRY insertion region, Sdc1-DPY30 interacting region, and DPY30 dimer. The study also uncovers different states of MLL1-WRAD during its assembly. The docking of subunits in the complex differs when bound to ubiquitinated nucleosomes, indicating the role of ubiquitin in promoting the formation of the active complex.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
James K. Fields, Chad W. Hicks, Cynthia Wolberger
Summary: Post-translational modification of histones, including methylation and monoubiquitination, plays a crucial role in transcription regulation. Methylation of H3K4 and H3K79 activates transcription, while methylation of H3K27 represses transcription. These modifications are dependent on prior monoubiquitination of specific histone residues, leading to a phenomenon called histone crosstalk. Recent studies have provided new insights into the mechanisms of how these modifications regulate the activity of various histone-modifying enzymes.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Fan Zhao, Chad W. Hicks, Cynthia Wolberger
Summary: This study reveals the mechanism by which the E3 ligase Bre1 directs monoubiquitination of histone H2B at K123 by the E2 ubiquitin-conjugating enzyme Rad6, and compares the roles of other dimeric E3 ligases, suggesting a mechanism of tuning histone residue specificity.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Michael Morgan, Tatsuya Ikenoue, Hiroaki Suga, Cynthia Wolberger
Summary: The Spt-Ada-Gcn5 acetyltransferase (SAGA) transcriptional coactivator contains a subcomplex called the deubiquitinating enzyme (DUB) module that can remove ubiquitin from histone H2B-K120. The human DUB module includes the catalytic subunit ubiquitin-specific protease 22 (USP22), which is overexpressed in certain cancers resistant to existing therapies. By screening a large library of cyclic peptides, potent inhibitors of USP22 were identified. The top hit showed high specificity for USP22 and was able to enter human cells and inhibit H2B deubiquitination.
CELL CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Physical
Carmen Ka Man Tse, Jun Xu, Liang Xu, Fu Kit Sheong, Shenglong Wang, Hoi Yee Chow, Xin Gao, Xuechen Li, Peter Pak-Hang Cheung, Dong Wang, Yingkai Zhang, Xuhui Huang
Article
Biology
Melesse Nune, Michael T. Morgan, Zaily Connell, Laura McCullough, Muhammad Jbara, Hao Sun, Ashraf Brik, Tim Formosa, Cynthia Wolberger