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Integrative expression, survival analysis and cellular miR-2909 molecular interplay in MRN complex check point sensor genes (MRN-CSG) involved in breast cancer

Published:September 08, 2022DOI:https://doi.org/10.1016/j.clbc.2022.09.002

      Abstract

      Background

      Breast cancer, an emerging global challenge, is evidenced by recent studies of miRNAs involvement in DNA repair gene variants (MRE11, RAD50 and NBN as checkpoint sensor genes (CSG) – MRN-CSG). The identification of various mutations in MRN-CSG and their interactions with miRNAs is still not understood. The emerging studies of miR-2909 involvement in other cancers led us to explore its role as molecular mechanistic marker in breast cancer.

      Methods

      The genomic and proteomic data of MRN-CSG of breast cancer patients (8426 samples) was evaluated to identify the mutation types linked with the patient's survival rate. Additionally, molecular, 3D-structural and functional analysis was performed to identify miR-2909 as regulator of MRN-CSG.

      Results

      The genomic and proteomic data analysis shows genetic alterations with majority of missense mutations [RAD50 (0.7%), MRE11 (1.5%), and NBN (11%)], though with highest MRE11 mRNA expression in invasive ductal breast carcinoma as compared to other breast cancer types. The Kaplan–Meier survival curves suggest higher survival rate for unaltered groups as compared to the altered group. Network analysis and disease association of miR-2909 and MRN-CSG shows strong interactions with other partners. The molecular hybridization between miR-2909-RAD50 and miR-2909-MRE11 complexes showed thermodynamically stable structures. Further, argonaute proteins, involved in RNA silencing, docking studies with miR-MRE11-mRNA and miR-RAD50-mRNA hybridized complexes showed strong binding affinity.

      Conclusion

      The results suggest that miR-2909 forms strong thermodynamically stable molecular hybridized complexes with MRE11 and RAD50 mRNAs which further strongly interacts with argonaute protein suggest potential molecular mechanistic role in breast cancer.
      Micro Abstract
      The MRN-CSG are the combination of MRE11, RAD50, and NBS1 genes encode MRN proteins which is important for maintaining genomic integrity and tumour suppression, although the extent and effect of their cancer-predisposing abnormalities are still unclear. MRN genes play a critical role in DNA double-strand break (DSB) repair by attracting the nuclear protein kinase ataxia telangiectasia mutant to DSB sites, resulting in DNA repair network activation. In the present study the MRN expression from clinical data showed the majority of the missense mutations, higher survival rate of unaltered group (non-mutated) as compared to the altered (mutated) group. The strong molecular hybridization between miR-2909 and MRN checkpoint sensor genes showed thermodynamic stability of formed complexes. The molecular and structural hybridization analyses of miR-2909/MRN-CSG complex reveal that miR-2909 can act as a DNA repair gene regulator towards MRN-CSG, which can act as potential biomarker for cancer diagnosis.

      Keywords

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