Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing.

Senthil Renganathan,Klaus Heese,Arne Kutzner,Subrata Pramanik,Rajasekaran Ekambaram,Pok-Son Kim

doi:10.3390/cancers13225870

Senthil Renganathan, Klaus Heese + Show 4 more

Open Access

https://doi.org/10.3390/cancers13225870

Copy DOI

Journal: Cancers	Publication Date: Nov 22, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Hanyang University, Örebro University, Kookmin University

Abstract

Simple SummaryPivotal factors that contribute to tumorigenesis were subjected to analysis by molecular modeling. In particular, the FAM72A-UNG2 protein–protein interaction was modeled to predict a potential solution for the treatment of cancer. We screened chemical libraries to identify withaferin B as a lead molecule capable of interfering with the FAM72A-UNG2 interaction, thus opening new therapeutic avenues for cancer.Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2 to prevent mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic bond and initiating the base excision repair pathway, thus maintaining genome integrity. In the present study, we determined a specific FAM72A-UNG2 heterodimer protein interaction using molecular docking and dynamics. In addition, through in silico screening, we identified withaferin B as a molecule that can specifically prevent the FAM72A-UNG2 interaction by blocking its cell signaling pathways. Our results provide an excellent basis for possible therapeutic approaches in the clinical treatment of cancer.

Highlights

Genomic uracil bases may occur from cytosine deamination or the misincorporation of dUMP residues during DNA replication [1]
Human UNG exists in two different isoforms, mitochondrial UNG1 and nuclear UNG2 association because the side chain (UNG2), that are both encoded from the same single 13.5-kb nuclear UNG gene as a result of two separate promoters and alternative splicing [12,13,14]
The obtained template for the N-terminal UNG2 3D peptide structure model (AA 1-313) was forwarded for UNG2 3D peptide structure modeling with I-TASSER [36,37] and Modeller v9.20 [38,39] software, and Chimera software was used as a graphical interface as described previously [34,35,39]

Summary

Introduction

Genomic uracil bases may occur from cytosine deamination or the misincorporation of dUMP residues during DNA replication [1]. A site-specific mutagenic approach was enabled to check the hot spot residues in the FAM72A protein and UNG2 (AA 1–45) peptide heterodimer interaction. Identified molecules obtained by the virtual screening were docked onto the FAM72A protein and UNG2 (AA 1–45) peptide heterodimer and/or FAM72A monomer using Schrödinger to depict binding mode and calculate binding energy [60,61].

Results

Conclusion