scholarly journals A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maximilian Fottner ◽  
Maria Weyh ◽  
Stefan Gaussmann ◽  
Dominic Schwarz ◽  
Michael Sattler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Proteins ◽  
Post Translational Modification ◽  
Functional Impact ◽  
Target Proteins ◽  
Cellular Processes ◽  
Damage Repair ◽  
Powerful Approach ◽  
Almost All ◽  
Stepwise Assembly

AbstractThe post-translational modification of proteins with ubiquitin (Ub) and Ub-like modifiers (Ubls) represents one of the most important regulators in eukaryotic biology. Polymeric Ub/Ubl chains of distinct topologies control the activity, stability, interaction and localization of almost all cellular proteins and elicit a variety of biological outputs. Our ability to characterize the roles of distinct Ub/Ubl topologies and to identify enzymes and receptors that create, recognize and remove these modifications is however hampered by the difficulty to prepare them. Here we introduce a modular toolbox (Ubl-tools) that allows the stepwise assembly of Ub/Ubl chains in a flexible and user-defined manner facilitated by orthogonal sortase enzymes. We demonstrate the universality and applicability of Ubl-tools by generating distinctly linked Ub/Ubl hybrid chains, and investigate their role in DNA damage repair. Importantly, Ubl-tools guarantees straightforward access to target proteins, site-specifically modified with distinct homo- and heterotypic (including branched) Ub chains, providing a powerful approach for studying the functional impact of these complex modifications on cellular processes.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

scholarly journals Structural basis for UFM1 transfer from UBA5 to UFC1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Manoj Kumar ◽  
Prasanth Padala ◽  
Jamal Fahoum ◽  
Fouad Hassouna ◽  
Tomer Tsaban ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Structural Basis ◽  
Adenylation Domain ◽  
Post Translational Modification ◽  
Target Proteins ◽  
Cellular Processes ◽  
Enzyme Cascade ◽  
Linear Sequence ◽  
C Terminus

AbstractUfmylation is a post-translational modification essential for regulating key cellular processes. A three-enzyme cascade involving E1, E2 and E3 is required for UFM1 attachment to target proteins. How UBA5 (E1) and UFC1 (E2) cooperatively activate and transfer UFM1 is still unclear. Here, we present the crystal structure of UFC1 bound to the C-terminus of UBA5, revealing how UBA5 interacts with UFC1 via a short linear sequence, not observed in other E1-E2 complexes. We find that UBA5 has a region outside the adenylation domain that is dispensable for UFC1 binding but critical for UFM1 transfer. This region moves next to UFC1’s active site Cys and compensates for a missing loop in UFC1, which exists in other E2s and is needed for the transfer. Overall, our findings advance the understanding of UFM1’s conjugation machinery and may serve as a basis for the development of ufmylation inhibitors.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals The importance of MLH1, MSH2, MSH6 and PMS2 in determining DNA damage response in digestive cancers

2021 ◽  
Vol 26 (1) ◽  
pp. 2289-2294
Author(s):  
FLAVIU PITU ◽  
SERGIU PASCA ◽  
CALIN POPA ◽  
AL HAJJAR NADIM
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Dna Damage Repair ◽  
R Package ◽  
Cellular Processes ◽  
Damage Repair ◽  
Digestive Cancers ◽  
Damage Response ◽  
The Common ◽  
Repair Pathways

Introduction: Genomic instability is a common feature across human cancers, but presents variation across different types of cancer, patients and cells of from the same tumor.This can be caused either by changes in the DNA damage repair pathways, aberrant histone modifications or methylation. The aim of this study was to determine the common mutated genes between digestive cancers that present genomic instability and to determine the biological processes in which these are implicated. Material and Methods: Mutational profiles for patients presenting digestive cancers and mutations in MLH1, MSH2, MSH6 and PMS2 were downloaded from the MSK impact cohort via cBioPortal. PANTHER was used to determine the GO SLIM processes in which the mutated genes are involved. R 3.5.3 and the R package circlize were used to generate chord diagrams. Results and Discussions: Considering the number of mutated genes from different digestive cancers it could be observed that the deregulated processes are general cellular processes, while when taking into consideration the fold change in overrepresentation of certain processes, the main deregulated processes are represented by DNA damage repair pathways, showing their overrepresentation in the selected cohort based on a few mutated genes. Conclusion: MLH1,MSH2,MSH6 and PMS2 mutations dictate the alterations in DNA damage repair pathways in digestive cancers.

scholarly journals Emerin Phosphorylation during the Early Phase of the Oxidative Stress Response Influences Emerin–BAF Interaction and BAF Nuclear Localization

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1415
Author(s):  
Vittoria Cenni ◽  
Stefano Squarzoni ◽  
Manuela Loi ◽  
Elisabetta Mattioli ◽  
Giovanna Lattanzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Stress Response ◽  
Cell Cycle Progression ◽  
Gene Mutations ◽  
Oxidative Stress Response ◽  
Post Translational Modification ◽  
Damage Repair ◽  
Inner Nuclear Membrane Protein ◽  
In Cells

Reactive Oxygen Species (ROS) are reactive molecules required for the maintenance of physiological functions. Oxidative stress arises when ROS production exceeds the cellular ability to eliminate such molecules. In this study, we showed that oxidative stress induces post-translational modification of the inner nuclear membrane protein emerin. In particular, emerin is phosphorylated at the early stages of the oxidative stress response, while protein phosphorylation is abolished upon recovery from stress. A finely tuned balance between emerin phosphorylation and O-GlcNAcylation seems to govern this dynamic and modulates emerin–BAF interaction and BAF nucleoplasmic localization during the oxidative stress response. Interestingly, emerin post-translational modifications, similar to those observed during the stress response, are detected in cells bearing LMNA gene mutations and are characterized by a free radical generating environment. On the other hand, under oxidative stress conditions, a delay in DNA damage repair and cell cycle progression is found in cells from Emery–Dreifuss Muscular Dystrophy type 1, which do not express emerin. These results suggest a role of the emerin–BAF protein platform in the DNA damage response aimed at counteracting the detrimental effects of elevated levels of ROS.

scholarly journals The structure and function of deubiquitinases: lessons from budding yeast

Open Biology ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 200279
Author(s):  
Harsha Garadi Suresh ◽  
Natasha Pascoe ◽  
Brenda Andrews
Keyword(s):  
Protein Quality ◽  
Budding Yeast ◽  
Post Translational Modification ◽  
Repair Gene ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
The Many ◽  
Key Aspects ◽  
And Function

Protein ubiquitination is a key post-translational modification that regulates diverse cellular processes in eukaryotic cells. The specificity of ubiquitin (Ub) signalling for different bioprocesses and pathways is dictated by the large variety of mono-ubiquitination and polyubiquitination events, including many possible chain architectures. Deubiquitinases (DUBs) reverse or edit Ub signals with high sophistication and specificity, forming an integral arm of the Ub signalling machinery, thus impinging on fundamental cellular processes including DNA damage repair, gene expression, protein quality control and organellar integrity. In this review, we discuss the many layers of DUB function and regulation, with a focus on insights gained from budding yeast. Our review provides a framework to understand key aspects of DUB biology.

scholarly journals Biophysical evaluation to categorize pathogenicity of cancer-predisposing mutations identified in the BARD1 BRCT domain

RSC Advances ◽  
2018 ◽  
Vol 8 (59) ◽  
pp. 34056-34068
Author(s):  
Rajan Kumar Choudhary ◽  
M. Quadir Siddiqui ◽  
Nikhil Gadewal ◽  
Nachimuthu Senthil Kumar ◽  
Ekaterina S. Kuligina ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Cell Cycle Checkpoint ◽  
Brct Domain ◽  
Cellular Processes ◽  
Damage Repair ◽  
Cycle Checkpoint

The BRCT domain of BARD1 (BARD1 BRCT) is involved in many cellular processes such as DNA damage repair (DDR) and cell-cycle checkpoint regulation.

scholarly journals ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors

2022 ◽  
Vol 23 (1) ◽  
pp. 523
Author(s):  
Sayaka Ueno ◽  
Tamotsu Sudo ◽  
Akira Hirasawa
Keyword(s):  
Dna Damage ◽  
Stress Responses ◽  
Current Knowledge ◽  
Critical Role ◽  
Atm Kinase ◽  
Synthetic Lethal ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Damage Repair ◽  
Cellular Stress Responses

Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

scholarly journals Towards a systematic map of the functional role of protein phosphorylation

2019 ◽  
Author(s):  
Cristina Viéitez ◽  
Bede P. Busby ◽  
David Ochoa ◽  
André Mateus ◽  
Marco Galardini ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Systematic Map ◽  
Gene Deletions ◽  
Chemical Genetic ◽  
Cellular Processes ◽  
Growth Profiles ◽  
Functional Relevance ◽  
Almost All

AbstractPhosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phosphomutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.

scholarly journals PARP inhibitors in gastric cancer: beacon of hope

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yali Wang ◽  
Kun Zheng ◽  
Yongbiao Huang ◽  
Hua Xiong ◽  
Jinfang Su ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Genome Instability ◽  
Parp Inhibitors ◽  
Synthetic Lethal ◽  
Strand Breaks ◽  
Cellular Processes ◽  
Single Strand Breaks ◽  
Damage Repair

AbstractDefects in the DNA damage response (DDR) can lead to genome instability, producing mutations or aberrations that promote the development and progression of cancer. But it also confers such cells vulnerable to cell death when they inhibit DNA damage repair. Poly (ADP-ribose) polymerase (PARP) plays a central role in many cellular processes, including DNA repair, replication, and transcription. PARP induces the occurrence of poly (ADP-ribosylation) (PARylation) when DNA single strand breaks (SSB) occur. PARP and various proteins can interact directly or indirectly through PARylation to regulate DNA repair. Inhibitors that directly target PARP have been found to block the SSB repair pathway, triggering homologous recombination deficiency (HRD) cancers to form synthetic lethal concepts that represent an anticancer strategy. It has therefore been investigated in many cancer types for more effective anti-cancer strategies, including gastric cancer (GC). This review describes the antitumor mechanisms of PARP inhibitors (PARPis), and the preclinical and clinical progress of PARPis as monotherapy and combination therapy in GC.

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