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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.
Clinical outcomes and characteristics of patients with TP53-mutated myelodysplastic syndromes
Published in Hematology, 2023
Lijuan Zhang, Kankan Chen, Yingying Li, Qiuni Chen, Wenting Shi, Tingting Ji, Hong Tao, Zhengmei He, Chunling Wang, Liang Yu
A total of 21 mutations were identified in the 19 cases, of which 17 (89.5%) cases harbored one mutation, 2 (10.5%) harbored two mutations (Table 2). Missense variant was the most common variant (17/21, 81.0%). The TP53 mutations were identified in the following sites: exon 4 in 3 (14.3%), exon 5 in 8 (38.1%), exon 6 in 4 (19.0%), exon 7 in 3 (14.3%), and exon 8 in 3 (14.3%) (Table 2). As shown in Table 2, DNA binding domains (exons 5–8) were the most common mutation sites in all cases. Among the 19 patients, 13 (68.4%) had other concurrent genetic mutations. TET2 was the most common mutation, detected in 6 (31.6%) patients, followed by DNMT3A in 3 (15.8%), SRSF2 in 3 (15.8%), U2AF1 in 3 (15.8%) cases. In addition, 19 cases had a median VAF of 43.22% (range, 7.46–88.2%) (Table 2). Recently, according to WHO 2022 guidelines, MDS with biallelic TP53 mutation (biTP53) has become a special subtype based on specific genetic abnormalities. Table 2 showed 10 patients with biTP53, and the clinical characteristics of biTP53 MDS patients will be analyzed detailedly in the future.
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].