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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
ZFPs can bind to DNA, RNA or other proteins, and variations in structure of the zinc finger serve to alter the binding specificity. Individual zinc finger domains normally occur as tandem repeats within ZFPs, with two, three, or more fingers comprising the DNA-binding domain of the protein. These tandem arrays bind in the DNA major groove of DNA and are typically spaced at 3-bp intervals. The α-helix of each domain (often called the “recognition helix”) makes sequence-specific contact with DNA bases, and residues from a single recognition helix can contact four or more bases to produce an overlapping pattern of contacts with adjacent zinc fingers.
Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
MEN1 patients manifest tumors of the anterior pituitary, the parathyroid glands, and the pancreatic islets. Adrenocortical and thyroid tumors are occasionally associated with the syndrome.1 The disorder is inherited in an autosomal dominant manner. The MEN1 gene has been mapped to chromosome 11q13 by linkage analysis.2 Two recent papers propose two different genes in the area of the chromosome linked to the syndrome. The first proposes a gene termed ZFM1 (for zinc finger gene in the MEN1 locus). The nucleotide sequence of the clone predicts a gene containing 14 exons and 623 amino acids, part of which appears to be a metal-binding domain (zinc finger motif), which is seen in nucleic acid-binding proteins. The putative protein has some similarity to the Wilms’ tumor gene product and the early growth response 2 protein.3 The other proposed gene is nearby on chromosome 11q13 and was located using deletion mapping of parathyroid tumors. This gene codes for a previously described protein, phospholipase C β3 (PLC β3), which, based on the activity of similar proteins, may be involved in signal transduction, intracellular calcium regulation, or activation of protein kinase C, which are in turn involved in cell growth and differentiation.4 There are no studies to date showing specific defects in either of these genes that cosegregate with MEN1 syndrome in affected families, so it is not yet clear which, if either, of these genes is responsible for the syndrome.
Molecular Biology Tools to Boost the Production of Natural Products
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Luzia Valentina Modolo, Samuel Chaves-Silva, Thamara Ferreira da Silva, Cristiane Jovelina da-Silva
Genome editing is a resource used to make changes in specific regions of a genome (e.g. insertion, substitution or deletion of DNA fragments) of a cell or organism for several purposes. This technique is based on the cleavage of the DNA double strand in targeted regions followed by the use of the own cell repair system to introduce precise mutations (Tan et al., 2018). In this scenario, reverse genetics (from gene to mutant phenotype) arises as a powerful tool to unravel gene function (Alonso and Ecker, 2006). In reverse genetics, a specific gene or gene product is disrupted or modified, and the plant phenotype is consequently determined (Figure 4.1; Tierney and Lamour, 2005). Some strategies of reverse genetics are described in the literature. Among them are included those that rely on the use of zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), homologous recombination, RNAi, T-DNA insertional mutagenesis, targeting induced local lesions in genome (TILLING) and clustered, regularly interspaced, short palindromic repeat-Cas9 (CRISPR-Cas9) (Abbai et al., 2017).
Molecular study and genotype–phenotype in Chinese female patients with 46, XY disorders of sex development
Published in Gynecological Endocrinology, 2021
Junke Xia, Jing Wu, Chen Chen, Zhenhua Zhao, Yanchuan Xie, Zhouxian Bai, Xiangdong Kong
Androgens are key elements of male sex differentiation. After normal testicle development, leydig cells produce testosterone, which promotes genital virilization [22]. Mutations in the AR gene (OMIM #313700) result in a loss-of-function androgen, leading to androgen insensitivity syndrome (AIS), which is the most common cause of 46, XY DSDs. The phenotype ranges from normal female external genitalia in the complete form (CAIS) to normal male external genitalia associated with infertility and/or gynecomastia in the mild form (MAIS) [23,24]. Here, a novel missense variant (Cys580Ser) was identified in a highly conserved residue of the DBD, which contains two zinc finger configurations [24]. Four cysteine residues coordinately bind to a zinc ion in each of the two zinc fingers. Hence, we hypothesized that cysteine change affected the three-dimensional structure of the first zinc finger and led to loss of DBD activity.
Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2021
Anne-Fleur E. Schneider, Annemieke Aartsma-Rus
DNA binding domains that are amply present in the human genome are those targeted by zinc fingers. Zinc finger nucleases are thus a more straightforward approach to achieve targeted editing. For DMD, zinc finger nucleases have been used to delete exon 51 from the DMD gene in myoblasts of DMD patients [94]. However, some off-target effects were also found. To increase specificity, several zinc finger domains can be combined, but this does not eliminate non-specificity completely due to context dependency. Recognition and cleavage of the target sequence is not only determined by the matching zinc finger domain but also by neighboring sequences. Furthermore, zinc finger nucleases sometimes have a bias for recognition of a particular sequence, making it harder to design them for any given target. Moreover, efficiency of the zinc finger delivery has proven to be relatively low [95].
Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment
Published in Expert Review of Clinical Immunology, 2019
Margot C.E. Polderdijk, Michiel Heron, Saskia Kuipers, Ger T. Rijkers
Maitre et al. [74] described many mutations that have not been associated with HCL before or at least to a very limited extent. The KDM6A mutation is located on the X chromosome, and could perhaps explain the male predominance of HCL. The mutation results in loss of function of a lysine demethylase protein, which may sensitize tumor cells to EZH2 inhibitors. The KLF2 mutation appears in 10–16% of patients. This gene is involved in inhibition of the NFκB pathway, as well as B-cell homing to lymph nodes. The mutations found are either in the zinc finger domain or nuclear localization signal, and both lead to loss of function of the protein. The exact mechanisms are unknown, but it is consistent with the NFκB activation that is reported in HCL [76]. The mutation is found also in splenic marginal zone lymphoma. U2AF1 splicing factor mutations are reported by Durham et al. [27], but only in HCLv. Similarly, these researchers found CCND3 mutations in 13% of HCLv patients, which led to loss of the PEST domain and increased expression of CCND3. Elevated levels of the related CCND1 mRNA have been found also, but it is not clear what the implications for this are [77]. The product of CCND1, cyclin D1, is sometimes used as a diagnostic marker for HCL.