Abstract
Cancer occurs when a portion of the body's cells begin to divide uncontrollably and spread into surrounding tissues. Most common reason for growth is genetic mutations. DNA Double Strand Breaks (DSB) brought about by ionizing radiation or other cancer-causing chemicals are one of the unavoidable changes bringing about carcinogenesis. Efficient DNA repair is generally gainful for living beings but in cancer therapy efficient DNA repair challenges the activity of radio and chemotherapies based on DNA damaging agents with cells becoming resistant to drugs. DSB repair pathways therefore serve as critical components for tumor suppression. Cells accomplish error-free repair of DNA DSBs by homologous recombination (HR) repair pathway. Mammalian proteins involved in HR include BRCA1, BRCA2, RAD51 and the RAD51 paralogs. Targeting the function of these proteins can, therefore, offer solution to resistance to anti-cancer treatment, thereby improving the efficiency of chemotherapy and preventing reoccurrence of tumors. RAD51 and its paralogs are central players of the pathway and are targeted for functional disruption. Sequence analysis of RAD51 proteins demonstrates regions within the ATPase domain that are conserved across species and amongst various paralogs. Multiple CHK1/CHK2 phosphorylation sites are present in all the paralogs with at least one of the site in close proximity to the ATPase domain. Inhibitors are identified that bind to the ATP-binding pocket of RAD51 paralogs thereby affecting its hydrolysis. The RAD51 protein interaction with BRCA2 protein is another important target through peptides designed against evolutionarily conserved regions of BRCA2, BRC4. Combinatorial targeting of the function of proteins involved in HR in combination with DNA damaging agents can, therefore, offer solution to radio and chemoresistance, thereby improving the efficiency of chemotherapy and preventing re-occurrence of tumors.
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All data generated or analysed during this study are included in this published article. However, any data or analysis from the current study can be made available from the corresponding author upon reasonable request.
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Funding
This study was supported by the Department of Science Technology-Science and Engineering Research Board (DST-SERB), Govt. of India, YSS/2015/001281, Preeti Rajesh, SB/YS/LS-168/2013, Harsimran Kaur.
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Kaur, H., Kaur, H., Rajesh, P. et al. In Silico design and characterization of RAD51 protein inhibitors targeting homologous recombination repair for cancer therapy. GENOME INSTAB. DIS. 4, 289–302 (2023). https://doi.org/10.1007/s42764-023-00106-4
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DOI: https://doi.org/10.1007/s42764-023-00106-4