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International Journal of Molecular... Sep 2023The evolving history of BRCA1 research demonstrates the profound interconnectedness of a single protein within the web of crucial functions in human cells. Mutations in... (Review)
Review
The evolving history of BRCA1 research demonstrates the profound interconnectedness of a single protein within the web of crucial functions in human cells. Mutations in BRCA1, a tumor suppressor gene, have been linked to heightened breast and ovarian cancer risks. However, despite decades of extensive research, the mechanisms underlying BRCA1's contribution to tissue-specific tumor development remain elusive. Nevertheless, much of the BRCA1 protein's structure, function, and interactions has been elucidated. Individual regions of BRCA1 interact with numerous proteins to play roles in ubiquitination, transcription, cell checkpoints, and DNA damage repair. At a cellular scale, these BRCA1 functions coordinate tumor suppression, R-loop prevention, and cellular differentiation, all of which may contribute to BRCA1's role in cancer tissue specificity. As research on BRCA1 and breast cancer continues to evolve, it will become increasingly evident that modern materials such as Bisphenol A should be examined for their relationship with DNA stability, cancer incidence, and chemotherapy. Overall, this review offers a comprehensive understanding of BRCA1's many roles at a molecular, cellular, organismal, and environmental scale. We hope that the knowledge gathered here highlights both the necessity of BRCA1 research and the potential for novel strategies to prevent and treat cancer in individuals carrying BRCA1 mutations.
Topics: Humans; Female; BRCA1 Protein; Breast Neoplasms; Ovarian Neoplasms; Breast; DNA Repair
PubMed: 37762577
DOI: 10.3390/ijms241814276 -
DNA Repair Jul 2024The ATP-dependent molecular chaperone Cdc48 (in yeast) and its human counterpart p97 (also known as VCP), are essential for a variety of cellular processes, including... (Review)
Review
The ATP-dependent molecular chaperone Cdc48 (in yeast) and its human counterpart p97 (also known as VCP), are essential for a variety of cellular processes, including the removal of DNA-protein crosslinks (DPCs) from the DNA. Growing evidence demonstrates in the last years that Cdc48/p97 is pivotal in targeting ubiquitinated and SUMOylated substrates on chromatin, thereby supporting the DNA damage response. Along with its cofactors, notably Ufd1-Npl4, Cdc48/p97 has emerged as a central player in the unfolding and processing of DPCs. This review introduces the detailed structure, mechanism and cellular functions of Cdc48/p97 with an emphasis on the current knowledge of DNA-protein crosslink repair pathways across several organisms. The review concludes by discussing the potential therapeutic relevance of targeting p97 in DPC repair.
Topics: Valosin Containing Protein; DNA Repair; Humans; Saccharomyces cerevisiae Proteins; DNA; Saccharomyces cerevisiae; DNA Damage; Cell Cycle Proteins; Nuclear Proteins; Adenosine Triphosphatases; DNA-Binding Proteins; Animals; Intracellular Signaling Peptides and Proteins
PubMed: 38744091
DOI: 10.1016/j.dnarep.2024.103691 -
Foods (Basel, Switzerland) Sep 2023(1) Background: The chicken egg is an animal product of great agronomic interest. The egg white and yolk constitute high-quality protein sources for humans with high...
(1) Background: The chicken egg is an animal product of great agronomic interest. The egg white and yolk constitute high-quality protein sources for humans with high digestibility and well-balanced amino acid profiles. Despite the egg white and yolk protein's undisputed value, research to unravel their full proteome content and its properties is still ongoing. We aimed to exhaustively analyze the proteome of egg white and yolk by applying intrinsic proteomics and bioinformatics approaches in order to unravel the full protein potential of this landmark food. (2) Methods: A total of 45 freshly laid, unfertilized, chicken eggs were subjected to nanoLC-MS/MS Orbitrap analysis following a peptide pre-fractionation step. A comprehensive bioinformatics processing step was undertaken towards elucidating potential activities and roles of identified molecules. In parallel, the literature was mined concerning all reported egg white and yolk protein identifications. (3) Results: Our analysis revealed 371 and 428 new proteins, reported for the first time to be present in the egg white and yolk, respectively. From the bioactivity standpoint, egg white and yolk proteins showed high enrichment for antioxidant and anti-inflammatory processes, while exerting high relevance for the apoptosis and focal adhesion pathways. (4) Conclusions: Egg white and yolk proteins exert diverse and multifaceted properties. A total of 799 proteins were reported for the first time as being part of the egg and yolk. Our novel protein data enriched those already published in the literature and the first ever chicken egg white and yolk Protein Atlas, comprising 1392 protein entries, was generated. This dataset will provide a cornerstone reference for future studies involving egg proteins.
PubMed: 37761179
DOI: 10.3390/foods12183470 -
The Journal of Biological Chemistry May 2024Adaptive immune responses comprise the activation of T cells by peptide antigens that are presented by proteins of the Major Histocompatibility Complex (MHC) on the... (Review)
Review
Adaptive immune responses comprise the activation of T cells by peptide antigens that are presented by proteins of the Major Histocompatibility Complex (MHC) on the surface of an antigen-presenting cell (APC). As a consequence of the T cell receptor (TCR) interacting productively with a certain peptide-MHC complex, a specialized cell-cell junction, the immunological synapse, forms and is accompanied by changes in the spatiotemporal patterning and function of intracellular signaling molecules. Key modifications occurring at the cytoplasmic leaflet of the plasma and internal membranes in activated T cells comprise lipid switches that affect the binding and distribution of proteins within or near the lipid bilayer. Here, we describe two major classes of lipid switches that act at this critical water/membrane interface. Phosphoinositides are derived from phosphatidylinositol, an amphiphilic molecule that contains two fatty acids chains and a phosphate group that bridges the glycerol backbone to the carbohydrate inositol. The inositol ring can be variably (de-)phosphorylated by dedicated kinases and phosphatates, thereby creating phosphoinositide signatures that define the composition and properties of signaling molecules, molecular complexes or whole organelles. Palmitoylation refers to the reversible attachment of the fatty acid palmitate to a substrate protein's cysteine residue. DHHC enzymes, named after the four conserved amino acids in their active site, catalyze this post-translational modification and thereby change the distribution of proteins at, between and within membranes. T cells utilize these two types of molecular switches to adjust their properties to an activation process that requires changes in motility, transport, secretion and gene expression.
PubMed: 38823638
DOI: 10.1016/j.jbc.2024.107428 -
Cell & Bioscience Feb 2024Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different... (Review)
Review
Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.
PubMed: 38347638
DOI: 10.1186/s13578-023-01189-y -
Science (New York, N.Y.) Dec 2023Kinetochores couple chromosomes to the mitotic spindle to segregate the genome during cell division. An error correction mechanism drives the turnover of...
Kinetochores couple chromosomes to the mitotic spindle to segregate the genome during cell division. An error correction mechanism drives the turnover of kinetochore-microtubule attachments until biorientation is achieved. The structural basis for how kinetochore-mediated chromosome segregation is accomplished and regulated remains an outstanding question. In this work, we describe the cryo-electron microscopy structure of the budding yeast outer kinetochore Ndc80 and Dam1 ring complexes assembled onto microtubules. Complex assembly occurs through multiple interfaces, and a staple within Dam1 aids ring assembly. Perturbation of key interfaces suppresses yeast viability. Force-rupture assays indicated that this is a consequence of impaired kinetochore-microtubule attachment. The presence of error correction phosphorylation sites at Ndc80-Dam1 ring complex interfaces and the Dam1 staple explains how kinetochore-microtubule attachments are destabilized and reset.
Topics: Cell Cycle Proteins; Chromosome Segregation; Cryoelectron Microscopy; Kinetochores; Microtubule-Associated Proteins; Microtubules; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Protein Conformation
PubMed: 38060647
DOI: 10.1126/science.adj8736 -
Nucleic Acids Research Sep 2023In meiosis, Dmc1 recombinase and the general recombinase Rad51 are responsible for pairing homologous chromosomes and exchanging strands. Fission yeast...
In meiosis, Dmc1 recombinase and the general recombinase Rad51 are responsible for pairing homologous chromosomes and exchanging strands. Fission yeast (Schizosaccharomyces pombe) Swi5-Sfr1 and Hop2-Mnd1 stimulate Dmc1-driven recombination, but the stimulation mechanism is unclear. Using single-molecule fluorescence resonance energy transfer (smFRET) and tethered particle motion (TPM) experiments, we showed that Hop2-Mnd1 and Swi5-Sfr1 individually enhance Dmc1 filament assembly on single-stranded DNA (ssDNA) and adding both proteins together allows further stimulation. FRET analysis showed that Hop2-Mnd1 enhances the binding rate of Dmc1 while Swi5-Sfr1 specifically reduces the dissociation rate during the nucleation, about 2-fold. In the presence of Hop2-Mnd1, the nucleation time of Dmc1 filaments shortens, and doubling the ss/double-stranded DNA (ss/dsDNA) junctions of DNA substrates reduces the nucleation times in half. Order of addition experiments confirmed that Hop2-Mnd1 binds on DNA to recruit and stimulate Dmc1 nucleation at the ss/dsDNA junction. Our studies directly support the molecular basis of how Hop2-Mnd1 and Swi5-Sfr1 act on different steps during the Dmc1 filament assembly. DNA binding of these accessory proteins and nucleation preferences of recombinases thus dictate how their regulation can take place.
Topics: Cell Cycle Proteins; DNA; DNA, Single-Stranded; Meiosis; Rad51 Recombinase; Recombinases; Schizosaccharomyces
PubMed: 37395447
DOI: 10.1093/nar/gkad561 -
Biomedicine & Pharmacotherapy =... Sep 2023As the first histone acetyltransferase to be cloned and identified in yeast, general control non-depressible 5 (GCN5) plays a crucial role in epigenetic and chromatin... (Review)
Review
As the first histone acetyltransferase to be cloned and identified in yeast, general control non-depressible 5 (GCN5) plays a crucial role in epigenetic and chromatin modifications. It has been extensively studied for its essential role in regulating and causing various diseases. There is mounting evidence to suggest that GCN5 plays an emerging role in human diseases and its therapeutic potential is promising. In this paper, we begin by providing an introduction GCN5 including its structure, catalytic mechanism, and regulation, followed by a review of the current research progress on the role of GCN5 in regulating various diseases, such as cancer, diabetes, osteoporosis. Thus, we delve into the various aspects of GCN5 inhibitors, including their types, characteristics, means of discovery, activities, and limitations from a medicinal chemistry perspective. Our analysis highlights the importance of identifying and creating inhibitors that are both highly selective and effective inhibitors, for the future development of novel therapeutic agents aimed at treating GCN5-related diseases.
Topics: Humans; Histone Acetyltransferases; Neoplasms; Saccharomyces cerevisiae; Acetylation; Saccharomyces cerevisiae Proteins
PubMed: 37352700
DOI: 10.1016/j.biopha.2023.114835 -
Genes & Diseases Mar 2024The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is an acquired immune system of many bacteria and... (Review)
Review
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is an acquired immune system of many bacteria and archaea, comprising loci, genes, and its associated proteins. This system can recognize exogenous DNA and utilize the Cas9 protein's nuclease activity to break DNA double-strand and to achieve base insertion or deletion by subsequent DNA repair. In recent years, multiple laboratory and clinical studies have revealed the therapeutic role of the CRISPR/Cas9 system in neurological diseases. This article reviews the CRISPR/Cas9-mediated gene editing technology and its potential for clinical application against neurological diseases.
PubMed: 37692518
DOI: 10.1016/j.gendis.2023.03.017 -
Cancers Aug 2023YY1 is widely recognized as an intrinsically disordered transcription factor that plays a role in development of many cancers. In most cases, its overexpression is... (Review)
Review
YY1 is widely recognized as an intrinsically disordered transcription factor that plays a role in development of many cancers. In most cases, its overexpression is correlated with tumor progression and unfavorable patient outcomes. Our latest research focusing on the role of zinc ions in modulating YY1's interaction with DNA demonstrated that zinc enhances the protein's multimeric state and affinity to its operator. In light of these findings, changes in protein concentration appear to be just one element relevant to modulating YY1-dependent processes. Thus, alterations in zinc ion concentration can directly and specifically impact the regulation of gene expression by YY1, in line with reports indicating a correlation between zinc ion levels and advancement of certain tumors. This review concentrates on other potential consequences of YY1 interaction with zinc ions that may act by altering charge distribution, conformational state distribution, or oligomerization to influence its interactions with molecular partners that can disrupt gene expression patterns.
PubMed: 37686614
DOI: 10.3390/cancers15174338