Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
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).
Genome Editing for Genetic Lung Diseases
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
Zinc-finger nucleases (ZFNs) were discovered as one of the first useful tools for genome editing.3,26 A zinc-finger protein (ZFP) is composed of at least three zinc-finger domains, which provide sequence specificity by recognizing 3-bp DNA sequence through each domain.3,26 To create ZFN, ZFP is fused with the non-specific cleavage domain of the FokI endonuclease.3,26 A pair of ZFNs generate DSBs of DNA with the dimerization of the cleavage domain.3,26 In past decades, the editing efficiency of ZFNs has been significantly enhanced, and the engineering process has been considerably improved.3 However, sophisticated protein engineering is still required to target new genomic sequences.3 Later on, another powerful genome editing platform named transcription activator-like effector nucleases (TALENs) were developed.27 Each monomer of the DNA binding domain recognizes one specific nucleotide of the target sequence.27 The simplicity of one monomer-one nucleotide rule allows a faster design and assembly process of TALENs than ZFNs.27,28
Regulation of C-Reactive Protein, Haptoglobin, and Hemopexin Gene Expression
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
IL-6DBP belongs to the C/EBP class of transcription factors. These proteins are positive regulators of gene transcription and bind DNA as dimers. Their DNA binding domain consists of a dimerization interface, termed the leucine zipper, and a DNA contact surface containing clusters of basic amino acid residues. Several members of this family have recently been cloned and show substantial homology in their DNA binding domain (Figure 15). These include: C/EBP (C/EBPα),79,87 IL-6DBp (NF-IL-6,77 LAP,88 AGP/EBP,89 CRP2,90 and C/EBPβ85), and Ig/EBP-1104 (C/EBPγ), CRP1,90 and C/EBPδ.85) With the exception of Ig/EBP-1, which is expressed ubiquitously,104 the other members show a restricted, but partially overlapping, expression pattern in different tissues.85,88,90 The different members are capable of forming heterodimers in all intrafamilial combinations.85,88,90,104 Thus, heterodimeric interactions between the different members may potentially play an important role in the modulation of AP gene transcription. Indeed, functional interaction between IL-6DBP and C/EBP has been demonstrated (Section III.H). In the presence of equimolar amounts of IL-6DBPand C/EBP, the latter, which normally activates transcription in an IL-6-independent manner, is recruited into heterodimers whose activity is regulated by IL-6.
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].
Current and potential targets for drug design in the androgen receptor pathway for prostate cancer
Published in Expert Opinion on Drug Discovery, 2018
The AR is located on the X chromosome and its protein has four domains: N-terminal transactivation domain, a DNA-binding domain, the hinge region, and a ligand-binding domain [8]. The N-terminal transactivation domain has two transactivation regions: TAU1 and TAU 5 of which TAU5 accounts for most of the transcriptional activity [9]. The DNA-binding domain has two zinc finger motifs which help in DNA binding and in homodimerization. The hinge region is involved in the translocation of the receptor-ligand complex to the nucleus. The ligand-binding domain mediates the binding of putative ligands and defines the specificity of the ligands [10]. The TAU 5 unit of the N-terminal transactivation domain has been shown to be involved in continued AR signaling in castrate-resistant prostate cancer cells [11].
Common therapeutic advances for Duchenne muscular dystrophy (DMD)
Published in International Journal of Neuroscience, 2021
Arash Salmaninejad, Yousef Jafari Abarghan, Saeed Bozorg Qomi, Hadi Bayat, Meysam Yousefi, Sara Azhdari, Samaneh Talebi, Majid Mojarrad
Zinc-finger nucleases (ZFNs) are a broadly studied genome editing tool that are able to target genetic modification precisely [136,137]. A complete ZFN monomer is composed of a DNA binding domain and a catalytic domain of the FokI endonuclease. DNA binding domain is the array of Cys2-His2 zinc finger motifs and each motif recognize 3 base pair (bp) of DNA (DNA specificity of ZFN was expanded to 18 bp by developing of this motifs) [138]. Binding of two independent ZFN monomers to adjacent target DNA sequences on sense and antisense strands in a head-to-head position lead to site-specific double-strand breaks following dimerization of FokI at the target site. Recently some improvement has been used to increase the specificity of ZFN, such as limiting the spacer size between two ZFN monomers [139], designing of commit heterodimer FokI domains [140,141], and creating autonomous ZFN pairs [142].
Related Knowledge Centers
- DNA
- DNA Methylation
- DNA Repair
- DNA Replication
- Protein
- Protein Domain
- Chromatin
- Structural Motif
- Recognition Sequence
- Transcriptional Regulation