Awesome analysis
Brendan Curran in A Terrible Beauty is Born, 2020
At its most basic level, the genetic instructions of nuclear DNA are manifest as the proteins present within the cell. The precise function encoded in a gene is revealed only when the protein for which it codes has been identified. Luckily, the deep-rooted similarity of function in all living organisms means that particular gene sequences encode the same function no matter in which organism they occur – decode the gene function in one organism and you have almost certainly decoded it for them all. Yeast mutants have been generated and studied for decades, so the functions of many of their genes are already well known. This has allowed biologists who have never seen a nematode worm or extracted its DNA to use computer analysis to identify the functions encoded by hundreds of worm genes. They do so simply by calculating how closely a worm gene sequence resembles that of a yeast gene whose function has already been identified using traditional mutation studies.
Repair of Radiation Damage
Kedar N. Prasad in Handbook of RADIOBIOLOGY, 2020
It has been postulated27 that cultured mammalian cells repair radiation-induced DNA damage by the “cut-and-patch” mechanism. This mechanism of repair has been explained as follows: Radiation interacts with nuclear DNA. This interaction causes alteration of the bond structure of the DNA molecule. For modeling purposes, it was assumed that bond abnormalities occur at the site of interaction of radiation with DNA.Nucleases scan the DNA molecule for radiation-induced bond abnormalities and convert the bond abnormalities into actual breaks.If the break involved only one of the DNA strands, it is closed by the action of the repair enzyme. Thus, the single-strand DNA breaks are considered to be repairable radiation damage.If bond abnormalities occur in both DNA strands, this would result in a double-strand break. The double-strand break is considered lethal.
DNA-Binding Proteins and DNA-Synthesizing Enzymes in Eukaryotes
Lubomir S. Hnilica in Chromosomal Nonhistone Proteins, 2018
At least three different types of DNA polymerization can be classified: (1) replicative nuclear DNA synthesis, which is characterized by being semiconservative, symmetrical, bidirectional, and with short RNA-primed intermediates in the lagging strand; (2) repair DNA synthesis, occurring on both strands and restricted to short DNA gaps; (3) mitochondrial and adenovirus DNA synthesis, which is known to be continuous and proceeds in an asymmetrical way. DNA synthesis catalyzed by DNA polymerase α is a typical replicative type and is suggested to carry out replication of nuclear DNA. DNA polymerase α produces a short DNA fragment on ribo-primers in a quasiprocessive way. It may also be able to synthesize a longer DNA chain with the aid of other enzymes. On the contrary, DNA polymerase β works in a distributive way and incorporates nucleotides to the gaps on the activated DNA. Its properties suggest that DNA polymerase β performs a repair type of DNA synthesis. DNA polymerase α synthesizes DNA in vitro in a highly processive fashion. It can replicate mitochondrial and adenovirus DNAs, as well as synthesize the long, single-stranded DNA regions which might represent displaced strands of parental DNA being replicated asymmetrically. The details of the function of DNA polymerase α, β, and γ will be discussed later.
In vitro cytotoxicity of polyphenols from Datura innoxia aqueous leaf-extract on human leukemia K562 cells: DNA and nuclear proteins as targets
Published in Drug and Chemical Toxicology, 2020
Elham Chamani, Roshanak Ebrahimi, Khatereh Khorsandi, Azadeh Meshkini, Asghar Zarban, Gholamreza Sharifzadeh
Studies have shown that DNA is a pharmacological target of many of the drugs currently in clinical use or in advanced clinical trials (Hurley and Boyd 1988, Sirajuddin et al. 2013). In the eukaryotes, nuclear DNA interacts with histone proteins and forms a nucleoprotein complex known as chromatin. Chromatin arranges the nuclear genome into a restricted volume. The first level of chromatin organization consists of DNA-folding around histone proteins to shape the fundamental unit of the chromatin, the nucleosome (Hübner et al. 2013). In a nucleosome, 147 bp of DNA are enfolded in an octamer with two copies of four core histone proteins (H2A, H2B, H3, and H4) (Nair and Kumar 2012). As a linker histone, histone H1 surrounds the chromatosome by protecting the internucleosomal linker DNA near the nucleosome entry-exit point (Dixon et al. 2016, Kalashnikova et al. 2016).
Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs)
Published in OncoImmunology, 2018
Ricarda M. Hoffmann, Ben G. T. Coumbe, Debra H. Josephs, Silvia Mele, Kristina M. Ilieva, Anthony Cheung, Andrew N. Tutt, James F. Spicer, David E. Thurston, Silvia Crescioli, Sophia N. Karagiannis
The mechanism and location of toxin release depends on the type of linker. Non-cleavable linkers depend on degradation of the antibody with or without a portion of the linker to liberate the toxin from the ADC.6 However, cleavable linkers can release toxins through acidic conditions in the lysosome, reduction of the linker in the cytoplasm or cleavage by specific proteases.6 For ADCs containing cleavable linkers, the antibody-part of the ADC is either degraded once the toxin is cleaved or is recycled and released outside the cell in vesicles.4 Once the toxin is cleaved from the ADC, it enters the cytoplasm and can either bind to its molecular target in the cytoplasm (usually tubulin) or can cross into the nucleus and cause cell cycle arrest and apoptosis by interfering with DNA.7 Almost all payloads in clinical development are small hydrophobic molecules, that are able to cross biomembranes once cleaved from the ADC.8 Therefore, nuclear DNA as well as the cytoskeleton in the cytoplasm are suitable locations for the payload to interfere with critical cellular mechanisms resulting in cell death.
Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging
Published in Expert Opinion on Therapeutic Targets, 2022
Tongyu C Wikramanayake, Jérémy Chéret, Alec Sevilla, Mark Birch-Machin, Ralf Paus
Mitochondrial dysfunction is now known to be associated with multiple skin diseases beyond skin senescence and photoaging [184,185] (Table 1B and 3). This is because mitochondrial function impacts on keratinocyte terminal differentiation and thus epidermal barrier formation, and is essential for normal skin appendage development and homeostasis [191,234–236], in addition to providing cellular energy. Therefore, approximately 10% of patients with primary mitochondrial disorders present skin manifestations, such as hair and pigmentary abnormalities, skin rashes and acrocyanosis [109,184,185,189]. Dermatological disorders caused by mutations in nuclear DNA were summarized in an excellent review by Sreedhar and colleagues [109]. We have included the same disorders but organized them into disorders of the skin, or hair, or both for better clarity (Table 3).