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Nonhistone Nuclear Phosphoproteins
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
Rose and Jacob further studied the mechanism of enhancement of enzyme activity by phosphorylation. They found that the phosphorylated enzyme had an increased primer requirement and synthesized a greater number of poly(A) chains.184 However, the average poly(A) chain length did not increase. Thus, the rate, but not the extent of polyadenylation was increased by phosphorylation. Rose and Jacob suggest that the phosphorylated poly (A) polymerase has a greater affinity for poly A, thereby stabilizing the messenger RNA. This is consistent with their previous observation that the poly(A) polymerase is antigenically related and probably chemically identical to the poly(A) binding protein on polysomal messenger RNA.185 These data suggest that poly(A) polymerase plays multiple roles and may be located in the cytoplasm as well as the nucleus. The phosphorylation of poly(A) polymerase represents one of the clearest examples of a cause and effect relationship between phosphorylation and activity.
Cascade Regulation a Model of Integrative Control of Gene Expression in Eukaryotic Cells and Organisms
Published in M. Gerald, M.D. Kolodny, Eukaryotic Gene Regulation, 2018
We know, e.g., that the proteins associated with pre-mRNA and mRNA distribute all along the RNA backbone; they are not randomly distributed but bind to specific mRNA sequences; one specific protein interacts with the poly(A) tail of mRNA; most of these proteins are acidic; there is, however, a group of characteristic basic proteins which may play the role of histones at the pre-mRNA level.59 It is evident that this latter group, as well as the poly(A)-binding protein, correspond to service functions rather than to regulative signals. In contrast, the majority group of acidic proteins may very well represent regulative agents associating with signal sequences in the RNA. There is, however, nothing known at present about the location of the corresponding sites of these proteins in pre-mRNA and mRNA.
Biochemistry and Metabolism
Published in John D Firth, Professor Ian Gilmore, MRCP Part 1 Self-Assessment, 2017
John D Firth, Professor Ian Gilmore
The poly-A tail can influence the initiation of translation via the binding of special poly-A binding proteins, but it is not the place at which the ribosome is assembled, which occurs at the Cap structure at the 5′ end. It may be involved in mRNA stability.
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2022
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia, Débora Lanznaster, Hélène Blasco
Targeting TDP-43 for UPS degradation is also an important mechanism for proper turnover of TDP-43. The presence of robust ubiquitinated inclusions of TDP-43 suggests a strong dysfunction of the UPS. Tashiro and his colleagues reported that the degeneration of motoneurons and ALS-like symptoms in mice was primarily due to the impairment of the proteasome rather than autophagy functions [92]. Cleaved TDP-43 products were shown to be mainly degraded by the UPS, and their accumulation disrupts the normal function of this system [27]. Overexpression of poly(A)-binding protein nuclear 1 (PABPN1), a novel interaction partner of TDP-43, was found to increase the turnover of TDP-43 through the UPS, restoring the solubility and nuclear localization of TDP-43 [93]. Another study found that Thioridazine, which was previously used as an antipsychotic drug, was able to induce a proteasome-dependent clearance of TDP-43 aggregates in a cellular model of TDP-43 proteinopathy as well as reverse locomotor defects in a Drosophila model of ALS [94].
Indomethacin: an exploratory study of antiviral mechanism and host-pathogen interaction in COVID-19
Published in Expert Review of Anti-infective Therapy, 2022
Nishant Shekhar, Harpinder Kaur, Phulen Sarma, Ajay Prakash, Bikash Medhi
SARS-CoV-2 Nucleocapsid (N) protein enters the host cell along with viral RNA coating it from the phosphate backbone side to facilitate replication, process assembly, and release of the virus particle in the host cell. The La-related protein 1 (LARP1) and Poly-adenylate binding protein 1 (PABPC1) are RNA-binding proteins (RBP) that are involved in the regulation of translation of particular target mRNA transcripts downstream of the mTORC1 cascade. An exploratory study on the roles of LARP1 and PABP1 in the pathogenesis of Dengue virus (DENV) represents the pre-translation complex formation, where LARP1 and PABPC1 interact with the host eukaryotic translation initiation factors eIF4G and eIF4E forming a loop [44]. In this study, LARP1 was reported to positively regulate the DENV genome translation. Very recently, Lee et al. (2021) in their PPI interactome resource article identified LARP1 as an antiviral RBP binding to SARS-CoV-2 RNA molecule [45]. SARS-CoV-2-infected human Calu-3 lung epithelial cells consensome network reports that geometric fold change in LARP1 and PABPC1 expression was 1.15 and 1.21, respectively [35]. There was evidence of the interaction of PABPC1 and LARP1 with SARS & MERS proteins in virus-host interactome study as well [36]. Moreover, the CTD database reports that indomethacin co-treated with insulin, dexamethasone, 1-methyl-3-isobutylxanthine, and bisphenol F decreases the expression of PABPC1 and LARP1. However, no evidence of direct action of indomethacin was found for LARP1 and PABPC1.
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
In eukaryotic cells, the mRNA poly(A) tail recruits the poly(A)-binding protein and subsequently the eIF4G translation initiation complex to mediate translation [78]. For IVT mRNA used for mRNA therapeutics, the poly(A) tail is either encoded in the DNA template or added enzymatically to the mRNA after the in vitro transcription procedure as a separate step. DNA template-encoded poly(A) has the advantage of producing defined and reproducible poly(A) length [79]. In contrast, enzymatic post-transcriptional polyadenylation of mRNA could produce transcripts with different poly(A) lengths and therefore may not meet regulatory requirements [80]. Enzymatic polyadenylation of mRNA has to be performed under alkaline conditions. Since mRNA is susceptible to alkaline hydrolysis, the enzymatic polyadenylation method is known to produce mRNA of inferior quality, especially with longer transcripts (>3 kb) [81].