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Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
A DNA polymer is positively supercoiled when it contains more than 10 bp per righthanded helical turn and is negatively supercoiled when it contains less than 10 bp per turn. The torsional stress imparted by negative supercoiling can induce Z-DNA formation.204–206 When a segment (call it A) of circular DNA is being transcribed or replicated it has to unwind, i.e., negatively supercoil. In unwinding, this forces a segment or segments near A to also negatively supercoil to some extent. The free energy state of negatively supercoiled DNA is higher than the normal, relaxed form of DNA, and thus it is less stable. Any process that reduces this superhelicity is therefore thermodynamically favored under these conditions. Z-DNA should behave in such a fashion, as it is thermodynamically stable at −12 bp per turn with regard to right-handed B-DNA. Thus it may provide the cushion necessary for segment A to unwind for transcription or replication while maintaining the stability of the overall structure of the chromosome. This would allow alternating purine-pyrimidine residues with the ability to flip from B to Z form to facilitate the unwinding of genes — a prelude to transcription.
Polynuclear Platinum Drugs
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
Due to the charged nature of polynuclear platinum, ranging from 2+ to 8+ for a complex such as XI, it is not surprising that DNA binding is significantly more rapid than that of cisplatin. The binding of polyamine-bridged dinuclear compounds is remarkably faster than BBR3464, suggesting a pre-association or electrostatic binding prior to covalent attachment. The proportion of interstrand crosslinks is not chain length-dependent but may be charge-dependent. The crosslinking ability at equal rb = 2 × 10−4 is: II < IV < III < IV-BOC < I, Table 1 [47]. Interestingly, in random sequence CT DNA the percentage of interstrand crosslinking appears to affect the amount of A-form present, unlike poly(dG)·poly(dC) which is capable of only intrastrand crosslinking assuming only G binding [43]. The ability to maintain unusual DNA conformations in solution is a unique characteristic of polynuclear platinum compounds. Cisplatin-induced bending of DNA maintains the B-form in solution [45]. Induced A-like conformations in vivo are theorized to be control mechanisms for DNA binding proteins like transcription factors. The biological function of Z-DNA is still not clearly defined [46], but the conformational “locking” into either A or Z-form by polynuclear platinum compounds is likely to have profound effects on DNA function.
Receptor-interacting protein kinase 1 (RIPK1) inhibitor: a review of the patent literature (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2023
Lijuan Xu, Wannian Zhang, Chunlin Zhuang
Currently, RIPK1 is one of the most intensively investigated members, except for its function as a node that drives cell survival and inflammatory response as well as apoptotic pathway and necroptotic cell death [11]. It is also reported that RIPK1 may modulate neuron autophagy in a traumatic brain injury (TBI) rat model through the NF-κB signaling pathway [12]. Additionally, RIPK1 is associated with pyroptosis. For example, inhibiting transforming growth factor-β-activated kinase 1 (TAK1) can trigger RIPK1-dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis) [13]. Except its kinase-dependent manner, RIPK1 also serves as a signaling scaffold to prevent the activation of caspase-8 (in apoptosis) and RIPK3 (in necroptosis) in a kinase – independent manner [14]. For example, in the intestine, RIPK1 acts as a scaffold to prevent epithelial cell apoptosis and preserve tissue integrity. In the skin, RIPK1 acts through its RIP homotypic interaction motif (RHIM) to counteract Z-DNA-binding protein/DNA-dependent activator of interferon regulatory factors (ZBP1/DAI)-dependent activation of RIPK3-MLKL-dependent necroptosis and inflammation [15].
Trial watch: STING agonists in cancer therapy
Published in OncoImmunology, 2020
Julie Le Naour, Laurence Zitvogel, Lorenzo Galluzzi, Erika Vacchelli, Guido Kroemer
Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) was first described in 2008 as a transmembrane component of the endoplasmic reticulum (ER) that senses cytosolic double-stranded DNA (dsDNA).1–4 This key adaptor protein in innate immune signaling5–8 can be activated by several cytoplasmic DNA sensors9–11 including cyclic GMP-AMP synthase (CGAS),12–15 Z-DNA binding protein 1 (ZBP1, best known as DAI), DEAD-box helicase 41 (DDX41), interferon-gamma inducible protein 16 (IFI16),16–18 LRR binding FLII interacting protein 1 (LRRFIP1),19,20 MRE11 homolog, double-strand break repair nuclease (MRE11),21 and perhaps protein kinase, DNA-activated, catalytic subunit (PRKDC, best known as DNA-PK),22,23 Among these sensors, CGAS has been studied in an extensive fashion. Mechanistically, the accumulation of ectopic dsDNA in the cytosol activates the enzymatic function of CGAS to generate cyclic GMP-AMP (cGAMP),15,24 as well as other cyclic dinucleotides (CDNs)25,26 bind to and activate STING, triggering a signal transduction pathway that culminates in the initiation of interferon regulatory factor 3 (IRF3)- or NF-κB-dependent transcriptional programs.27–30 Notably, CDN-bound STING also stimulates autophagy, an evolutionarily conserved mechanism for the preservation of cellular and organismal homeostasis,31–33 and such a function appears to be more ancient than the initiation of IRF3 and NF-κB transcriptional activity.34
Assessing regulated cell death modalities as an efficient tool for in vitro nanotoxicity screening: a review
Published in Nanotoxicology, 2023
Anton Tkachenko, Anatolii Onishchenko, Valeriy Myasoedov, Svetlana Yefimova, Ondrej Havranek
Importantly, a majority of studies have shown that necroptosis is linked to nanoparticles internalization and their ability to induce mitochondrial ROS (mitROS) production. MitROS generation, therefore, seems to have a pivotal role in nanoparticles-induced necroptosis (Johnson et al. 2015; Sonkusre and Cameotra 2017; Arya et al. 2018; Lee et al. 2019; Behzadi, Arasteh, and Bagheri 2020; Huang et al. 2020; Zhang, Hai, et al. 2021) (Figure 3). Nanoparticles-mediated ROS overgeneration triggers RIPK1 autophosphorylation and RIPK1/RIPK3/MLKL–dependent necroptosis (Arya et al. 2018; Kim et al. 2019). Moreover, nanoparticles-induced ROS-mediated oxidative protein modifications stimulate the accumulation of misfolded proteins and development of ER stress, which, in turn, could trigger necroptosis via apoptosis-inducing factor (AIF) activation (Huang et al. 2020). It has been reported that AIF is released from mitochondria, consequently translocated to the nucleus, and induces chromatin condensation, DNA degradation, and cellular lysis in a caspase-independent manner (Delavallée et al. 2011). Several alternative and related means of nanomaterials-induced necroptosis were also described. Huang et al. demonstrated the role of ROS/AIF/RIPK3 signaling in nanomaterials-induced necroptosis as an alternative to RIPK1 activation (Huang et al. 2020). Lee et al. documented the involvement of PI3K/AKT/eNOS signaling in autophagy-associated RIPK1-dependent necroptosis induction in cells exposed to nanomaterials (Lee et al. 2019). And Katifelis et al. reported the involvement of Z-DNA-binding protein 1 (ZBP1) and TNF/IRF1 signaling in nanoparticles-triggered necroptosis (Katifelis et al. 2022). To summarize, nanomaterials can activate necroptosis via multiple signaling pathways, however, the ROS-mediated induction seems to be the most critical mechanism of necroptosis-triggered nanomaterials toxicity.