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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Additionally, estimates suggest that there are ~1,800 DNA-binding transcription factors in the human genome (55). Of these, the regulatory transcription factors have a DNA-binding domain that recognises a specific DNA motif. Some common types of DNA-binding domain include the C2H2 zinc-finger, homeodomain and basic helix-loop-helix (55). Often, it is necessary for transcription factors to form homo- or heterodimers (protein-protein interactions) in order to create a correct DNA-binding motif. These transcription factors are further regulated by the binding of co-factors, such as the abovementioned PGC-1α, and its interaction with the transcription factors NRF-1, NRF-2, MEF2, ERRα and TFAM in the regulation of skeletal muscle gene expression. Moreover, a single session of aerobic exercise alters the DNA-binding activity of a variety of transcription factors, including MEF2 (56), NF-κB (57), and NRF-1 and NRF-2 (58).
Should Genome Editing Replace Embryo Selection Following PGT?
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
An improvement came in the early 1990s with the introduction of zinc finger nucleases (ZFNs) and transcription-activator-like effector nucleases (TALENs), which could be engineered in order to induce DSBs at specified sites. ZFNs utilize zinc finger protein domains that bind to a 3-bp motif in a modular manner, making them ideal as building units for the creation of sequence-specific DNA binding nucleases (19). TALENs, on the other hand, recognize a single base in each repeat domain, allowing up to four different domains to be mixed and matched to generate a novel DNA binding protein. However, both of these programmable nucleases are associated with an appreciable incidence of “off-target” effects, defined as non-specific cleavage of the DNA at locations other than the intended target site, potentially resulting in cytotoxicity (19,21). Furthermore, since the target specificity is determined by modification of the DNA binding domain, the application of these nucleases is limited to cases where successful engineering of binding domains is possible, at significant cost of time and resources.
ChIP-seq analysis
Published in Altuna Akalin, Computational Genomics with R, 2020
As explained in Chapter 1, gene expression is controlled by a special class of genes called transcription factors - genes which control other genes. Transcription factor genes encode proteins which can bind to the DNA, and control whether a certain part of DNA will be transcribed (expressed), or stay silent (repressed). They program the expression patterns in each cell. Transcription factors contain DNA binding domains, which are specifically folded protein sequences which recognize specific DNA motifs (a short nucleotide sequence). Such sequence binding imparts transcription factors with specificity, transcription factors do not bind everywhere on the DNA, rather they are localized to short stretches which contain the corresponding DNA motif.
Investigating protein–excipient interactions of a multivalent VHH therapeutic protein using NMR spectroscopy
Published in mAbs, 2022
Jainik Panchal, Bradley T. Falk, Valentyn Antochshuk, Mark A. McCoy
From a protein engineering perspective, molecules with multiple well-defined binding domains can be produced by a wide variety of strategies.33 In one approach, Fc-directed modifications in traditional IgG mAbs can lead to bispecific mAbs with improved properties.34 Unique scaffolds can be created by linking together antibody fragments or small protein scaffolds that have been evolved or designed to yield high-affinity target/antigen interactions.35 Due to their smaller size, architecture and lack of Fc binding, novel therapeutic protein scaffolds, such as VHH fragments can potentially bind to targets that are difficult for traditional antibodies to reach, for example, providing access to regions of tumor micro-environments. Multivalent molecules engineered from novel scaffolds can potentially bind to and crosslink multiple cell surface receptors to enhance signaling in the same cell; alternatively, different specificities can be selected to crosslink different cell types. Multiple epitopes on the same target protein can potentially be engaged. Moreover, MV-VHH proteins potentially offer an engineering approach to combination therapies, delivering multiple therapeutic proteins with different mechanisms.
Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2021
Rutika Mehta, Anthony C Wood, James Yu, Richard Kim
A large collection of proteins has been identified that are crucial to the execution of the DDR. Some of the most important players in the DDR are the PARP enzymes. There are 17 PARP family members with PARP1 holding the most prominent role in the DDR accounting for 80% of PARP activity [23]. However, PARP2 and PARP3 also share some overlapping responsibility in the DDR to a lesser extent [24]. While it does have a role in the repair of DSBs, PARP1’s primary function is to participate in the correction of SSBs [25]. PARP1 enzyme has two domains: (a) DNA-binding domain and the (b) catalytic domain. Upon binding of damaged DNA to the DNA-binding domain, the catalytic function of the enzyme is activated which leads to the generation of extensive negatively charged poly(ADP-Ribose) chains (PAR chains) that attach to nearby proteins through a process known as PARylation. This PARylation modifies the chromatin structure to support repair recruiting important SSB repair proteins, such as XRCC1, to the site of damage. PARP1 eventually PARylates itself (autoPARylation) and is released from the corrected DNA [22,25,26]. These steps are essential for cancer cells to respond to damages in the DNA induced by cytotoxic treatments or radiation. In vitro and in-vivo studies have shown that cells with loss of both alleles of PARP while may be conducive to survival under normal conditions can suffer extensive damage when exposed to alkylating chemotherapy and ionizing radiation [27].
Association between oestrogen receptors and female temporomandibular disorders
Published in Acta Odontologica Scandinavica, 2020
Erika Calvano Küchler, Michelle Nascimento Meger, Marjorie Ayumi Omori, Jennifer Tsi Gerber, Evandro Carneiro Martins Neto, Nilza Cristina da Silva Machado, Rafael Corrêa Cavalcante, Lucas Ribeiro Teixeira, Maria Bernadete Stuani, Paulo Nelson Filho, Delson João da Costa, Juliana Feltrin de Souza, João Armando Brancher, Jorge Esquiche León, Rafaela Scariot
Oestrogens regulate various physiological processes, including cell growth, reproduction, differentiation and development. They also consist of three functional domains: the NH2-terminal domain, the DNA-binding domain and the COOH-terminal ligand-binding domain. Cellular signalling of oestrogens is mediated through oestrogens receptors (ERs), which have two forms: α and β [7]. The oestrogen receptor alpha (ERα) is codified by ESR1 gene, while oestrogen receptor beta (ERβ) is codified by ESR2 gene. The receptor ERα acts as a regulator of intracellular mediators and is found in cartilage tissue, intra-articular osteocytes [8,9] and in mandibular condylar fibrocartilage [10–12]. ERα is expressed in all cells of the mandibular condylar fibrocartilage demonstrating the possible importance that this receptor must play in oestrogen signalling in the temporomandibular joint (TMJ) [10]. The ERβ is found in the ovary, central nervous system, cardiovascular system, lung, male reproductive organs, prostate, colon, kidney, skeletal and immune system. ERβ secretes endocrine factors that support bone development or remodelling [2,13,14]. Additionally, previous studies indicated that ERβ mediated oestrogen’s role on condylar fibrocartilage cell proliferation [15].