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Order Martellivirales: Virgaviridae
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The largest ORF encodes a replication protein with conserved methyltransferase and helicase domains, an arrangement typical of alpha-like viruses. This protein is translated directly from the genomic RNA. In viruses of all genera except Hordeivirus, the RNA dependent RNA polymerase is expressed as the C-terminal part of this protein by readthrough of a leaky stop codon. The movement proteins and the capsid protein are expressed from separate subgenomic mRNAs (Adams et al. 2017).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
ATR is particularly important for the repair of single-strand breaks due to RS at the replication fork which can cause replication to stall or slow down. Furthermore, if the damage is not repaired, then the replication fork can collapse leading to cell death. Initially, ATR is recruited to a complex of RPA (Replication Protein A) and single-stranded DNA at the site of damage. A conformational change of ATR brought about by ATR activator proteins then triggers a multifaceted response through the activation of numerous downstream effector proteins, including the CHK1 kinase. Studies have suggested that different activator proteins may initiate different pathways of ATR activation in response to distinct types of DNA damage. Through CHK1, ATR is able to arrest cell cycle at the G2/M and S checkpoints, thus reducing RS by blocking global duplication of DNA and triggering the appropriate DNA-repair pathways.
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
The nature of the lesion dictates the presence of the initial damage-sensing protein. For example, base lesions are recognized by specific glycosylases that are designed to identify and remove the damaged base, while the loss of bases or phosphodiester bonds within DNA quickly activates poly (ADP-ribosylation)-polymerases (PARPs). DSBs are recognized by the MRN complex, consisting of three proteins: MRE11, RAD50 and NBS1. Notably, the NBS1 protein is the product of the gene that is mutated in Nijmegen breakage syndrome (NBS). As its central function in DSB recognition and repair suggests, patients with this syndrome are radiosensitive. The Ku proteins (Ku70 and 80) can also recognize and efficiently bind the ends of DSBs. Single-stranded DNA regions generated during replication or during DSBR are coated by the RPA complex. These initial DNA damage sensing events influence repair pathway choice and dictate DDR signalling through engaging different signal transduction proteins and mechanisms.
Hypoxia increases mutational load of breast cancer cells through frameshift mutations
Published in OncoImmunology, 2020
Goutham Hassan Venkatesh, Pamela Bravo, Walid Shaaban Moustafa Elsayed, Francis Amirtharaj, Bartosz Wojtas, Raefa Abou Khouzam, Husam Hussein Nawafleh, Sandeep Mallya, Kapaettu Satyamoorthy, Philippe Dessen, Filippo Rosselli, Jerome Thiery, Salem Chouaib
Our studies were in line with the findings from other report23 that hypoxia alone is not sufficient to induce DNA double-strand breaks. However, we noticed the upregulation of ROS pathway specifically in intermittent hypoxic cells in both cell lines. Earlier studies have demonstrated that the hypoxia and reoxygenation after hypoxic stress is one of the key factors for replication stress in tumor cells.24,25 Further, the increase in RPA32 was higher in intermittent cells in both cell types, indicating the presence of higher replication stress. Increase in RPA32 levels can be attributed to the increase in ROS levels. Replication stress is characterized by the presence of stalled forks with long stretches of ssDNA.9 Replication Protein A is one of the initial responders to replication stress and binds to ssDNA for stabilization. Despite the replication stress, some cells can bypass genetic lesions and continue replicating by repriming the lesion. Cells that proliferate even in low oxygen levels, with compromised DNA repair mechanisms acquire increased genetic instability.14 Together, reoxygenation induced DNA damage, hypoxic replication stress, increase in ROS levels, and downregulation of DNA repair pathways contribute to the genomic instability in breast cancer cells.
AID Biology: A pathological and clinical perspective
Published in International Reviews of Immunology, 2018
Meenal Choudhary, Anubhav Tamrakar, Amit Kumar Singh, Monika Jain, Ankit Jaiswal, Prashant Kodgire
Numerous cofactors related to AID have been identified that govern the target specificity of AID. The germinal center-associated nuclear protein (GANP) that is induced in germinal center B-cells during the immune response transports AID to the nucleus and assists in recruiting AID to actively transcribing IgV genes during SHM [76]. Replication protein A (RPA) is a highly conserved single-stranded DNA-binding protein in eukaryotes which plays an essential role in DNA replication and downstream DNA recombination and repair pathways [77]. RPA associated with the single-stranded DNA template undergoing transcription mediates access of the deaminase enzyme to its DNA substrate [78]. Vuong and co-researchers have shown that the interaction between AID and RPA is mediated by PKA that phosphorylates AID at the serine residue (S38) [79]. AID targets RNA Polymerase II stalled sites in DNA through its association with Spt5 [80]. Spt5-depletion impaired AID-polII interaction and diminished AID-recruitment to its Ig switch regions and non-Ig genes. Genome-wide ChIP-seq studies identified that regions with high Spt5 levels corresponded with sites of elevated AID localization and that genomic enrichment of Spt5 at stalled polII sites are an indication of AID-mediated mutations [80]. The essential role of SR-proteins in the immune response is also reported, where a splice isoform of SRSF1 (SRSF1-3) acts as a cofactor in inducing hypermutation at IgV genes in DT40 cells [81]. Albeit precise mechanisms governing AID targeting to immunoglobulin genes are yet to be resolved, several studies state about factors contributing to its specific recruitment to target DNA.
Application of next-generation sequencing in the diagnosis of gastric cancer
Published in Scandinavian Journal of Gastroenterology, 2022
Narges Moradi, Solmaz Ohadian Moghadam, Siamak Heidarzadeh
A recent study by Zhang and Yu has discussed the importance of replication protein A (RPA), a family of DNA-binding proteins, in GC prognosis concluding that the expression levels of RPA1, 2 and 3 are meaningfully elevated in GC tissues in comparison with normal tissues thus RPAs can be used as efficient prognostic factors and indicators of immunological diseases [88].