Molecular avenues in targeted doxorubicin cancer therapy

2020 ◽  
Vol 16 (11) ◽  
pp. 687-700 ◽  
Author(s):  
Sayantani Roychoudhury ◽  
Ajay Kumar ◽  
Devyani Bhatkar ◽  
Nilesh Kumar Sharma
Keyword(s):  
Paradigm Shift ◽  
Molecular Genetic ◽  
Key Factors ◽  
Secondary Tumors ◽  
Evolutionary Changes ◽  
Repair Protein ◽  
Signaling Inhibitors ◽  
Dna Repair Protein ◽  
Environmental Adaptations ◽  
Health Disorders

In recent, intra- and inter-tumor heterogeneity is seen as one of key factors behind success and failure of chemotherapy. Incessant use of doxorubicin (DOX) drug is associated with numerous post-treatment debacles including cardiomyopathy, health disorders, reversal of tumor and formation of secondary tumors. The module of cancer treatment has undergone evolutionary changes by achieving crucial understanding on molecular, genetic, epigenetic and environmental adaptations by cancer cells. Therefore, there is a paradigm shift in cancer therapeutic by employing amalgam of peptide mimetic, small RNA mimetic, DNA repair protein inhibitors, signaling inhibitors and epigenetic modulators to achieve targeted and personalized DOX therapy. This review summarizes on recent therapeutic avenues that can potentiate DOX effects by removing discernible pitfalls among cancer patients.

scholarly journals Emerging Roles of RAD52 in Genome Maintenance

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1038 ◽  
Author(s):  
Manisha Jalan ◽  
Kyrie S. Olsen ◽  
Simon N. Powell
Keyword(s):  
Genome Stability ◽  
Genome Integrity ◽  
Repair Pathway ◽  
Genome Maintenance ◽  
Knock Out ◽  
Repair Protein ◽  
Attractive Therapeutic Target ◽  
Dna Repair Protein ◽  
Synthetically Lethal ◽  
Knock Out Mice

The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, especially in HR-deficient cells. One of the factors that appears to have a role in many of these pathways is human RAD52, a DNA repair protein that was previously considered to be dispensable due to a lack of an observable phenotype in knock-out mice. In later studies, RAD52 deficiency has been shown to be synthetically lethal with defects in BRCA genes, making RAD52 an attractive therapeutic target, particularly in the context of BRCA-deficient tumors.

scholarly journals A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M

2005 ◽  
Vol 37 (9) ◽  
pp. 958-963 ◽  
Author(s):  
Amom Ruhikanta Meetei ◽  
Annette L Medhurst ◽  
Chen Ling ◽  
Yutong Xue ◽  
Thiyam Ramsing Singh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Complementation Group ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Human Ortholog

Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT

2016 ◽  
Vol 55 (8) ◽  
pp. 2911-2915 ◽  
Author(s):  
Chao Wang ◽  
Daniel Abegg ◽  
Dominic G. Hoch ◽  
Alexander Adibekian
Keyword(s):  
Dna Repair ◽  
Selective Inhibitor ◽  
Repair Protein ◽  
Dna Repair Protein

Partial characterization of the DNA repair protein complex, containing the ERCC1, ERCC4, ERCC11 and XPF correcting activities

1995 ◽  
Vol 337 (1) ◽  
pp. 25-39 ◽  
Author(s):  
A.J. van Vuuren ◽  
E. Appeldoorn ◽  
H. Odijk ◽  
S. Humbert ◽  
V. Moncollin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Protein Complex ◽  
Partial Characterization ◽  
Repair Protein ◽  
Dna Repair Protein

scholarly journals ROS induces NETosis by oxidizing DNA and initiating DNA repair

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dhia Azzouz ◽  
Meraj A. Khan ◽  
Nades Palaniyar
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Polymerase Activity ◽  
Neutrophil Activation ◽  
Neutrophil Extracellular Trap ◽  
Nuclear Antigen ◽  
Chromatin Decondensation ◽  
Genome Wide ◽  
Repair Protein ◽  
Dna Repair Protein

AbstractReactive oxygen species (ROS) are essential for neutrophil extracellular trap (NET) formation or NETosis. Nevertheless, how ROS induces NETosis is unknown. Neutrophil activation induces excess ROS production and a meaningless genome-wide transcription to facilitate chromatin decondensation. Here we show that the induction of NADPH oxidase-dependent NETosis leads to extensive DNA damage, and the subsequent translocation of proliferating cell nuclear antigen (PCNA), a key DNA repair protein, stored in the cytoplasm into the nucleus. During the activation of NETosis (e.g., by phorbol myristate acetate, Escherichia coli LPS, Staphylococcus aureus (RN4220), or Pseudomonas aeruginosa), preventing the DNA-repair-complex assembly leading to nick formation that decondenses chromatin causes the suppression of NETosis (e.g., by inhibitors to, or knockdown of, Apurinic endonuclease APE1, poly ADP ribose polymerase PARP, and DNA ligase). The remaining repair steps involving polymerase activity and PCNA interactions with DNA polymerases β/δ do not suppress agonist-induced NETosis. Therefore, excess ROS produced during neutrophil activation induces NETosis by inducing extensive DNA damage (e.g., oxidising guanine to 8-oxoguanine), and the subsequent DNA repair pathway, leading to chromatin decondensation.

scholarly journals Structure of the human DNA-repair protein RAD52 containing surface mutations

2016 ◽  
Vol 72 (8) ◽  
pp. 598-603 ◽  
Author(s):  
Mika Saotome ◽  
Kengo Saito ◽  
Keiichi Onodera ◽  
Hitoshi Kurumizaka ◽  
Wataru Kagawa
Keyword(s):  
Ring Structure ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Recombinational Repair ◽  
Repair Protein ◽  
Rad52 Protein ◽  
Dna Repair Protein ◽  
Binding Groove ◽  
Partially Unfolded

The Rad52 protein is a eukaryotic single-strand DNA-annealing protein that is involved in the homologous recombinational repair of DNA double-strand breaks. The isolated N-terminal half of the human RAD52 protein (RAD521–212) forms an undecameric ring structure with a surface that is mostly positively charged. In the present study, it was found that RAD521–212containing alanine mutations of the charged surface residues (Lys102, Lys133 and Glu202) is highly amenable to crystallization. The structure of the mutant RAD521–212was solved at 2.4 Å resolution. The structure revealed an association between the symmetry-related RAD521–212rings, in which a partially unfolded, C-terminal region of RAD52 extended into the DNA-binding groove of the neighbouring ring in the crystal. The alanine mutations probably reduced the surface entropy of the RAD521–212ring and stabilized the ring–ring association observed in the crystal.

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