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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Article Info
Publication History
Accepted:
September 3,
2022
Received in revised form:
August 25,
2022
Received:
May 4,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
