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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Nov 27

PMID 34831023

Citations 4

Authors

Senthil Renganathan

Subrata Pramanik

Rajasekaran Ekambaram

Arne Kutzner

Pok-Son Kim

Klaus Heese

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

FAM family gene prediction model reveals heterogeneity, stemness and immune microenvironment of UCEC.

Chi H, Gao X, Xia Z, Yu W, Yin X, Pan Y Front Mol Biosci. 2023; 10:1200335.

PMID: 37275958 PMC: 10235772. DOI: 10.3389/fmolb.2023.1200335.

Prognostic and Immunological Implications of FAM72A in Pan-Cancer and Functional Validations.

Bai Y, Cao K, Zhang P, Ma J, Zhu J Int J Mol Sci. 2023; 24(1).

PMID: 36613817 PMC: 9820597. DOI: 10.3390/ijms24010375.

Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma.

Zhou Q, Chen L, Yang L, Zhou H, Chen Y, Guo Y Front Oncol. 2022; 12:1046473.

PMID: 36483027 PMC: 9723133. DOI: 10.3389/fonc.2022.1046473.

A redox-sensitive iron-sulfur cluster in murine FAM72A controls its ability to degrade the nuclear form of uracil-DNA glycosylase.

Stewart J, Bhagwat A DNA Repair (Amst). 2022; 118:103381.

PMID: 35908367 PMC: 10996437. DOI: 10.1016/j.dnarep.2022.103381.

References

Beard W, Horton J, Prasad R, Wilson S . Eukaryotic Base Excision Repair: New Approaches Shine Light on Mechanism. Annu Rev Biochem. 2019; 88:137-162. PMC: 8956022. DOI: 10.1146/annurev-biochem-013118-111315. View

Zhang Y . I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008; 9:40. PMC: 2245901. DOI: 10.1186/1471-2105-9-40. View

Berna L, Alvarez-Valin F . Evolutionary volatile Cysteines and protein disorder in the fast evolving tunicate Oikopleura dioica. Mar Genomics. 2015; 24 Pt 1:47-54. DOI: 10.1016/j.margen.2015.07.007. View

Senthil R, Sakthivel M, Usha S . Structure-based drug design of peroxisome proliferator-activated receptor gamma inhibitors: ferulic acid and derivatives. J Biomol Struct Dyn. 2020; 39(4):1295-1311. DOI: 10.1080/07391102.2020.1740790. View

Rajasekaran E . CARd: Carbon distribution analysis program for protein sequences. Bioinformation. 2012; 8(11):508-12. PMC: 3398768. DOI: 10.6026/97320630008508. View

Webb B, Sali A . Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Protein Sci. 2016; 86:2.9.1-2.9.37. DOI: 10.1002/cpps.20. View

Kalathiya U, Padariya M, Baginski M . Structural, functional, and stability change predictions in human telomerase upon specific point mutations. Sci Rep. 2019; 9(1):8707. PMC: 6581908. DOI: 10.1038/s41598-019-45206-y. View

Kontoyianni M . Docking and Virtual Screening in Drug Discovery. Methods Mol Biol. 2017; 1647:255-266. DOI: 10.1007/978-1-4939-7201-2_18. View

Ji D, Xu M, Udenigwe C, Agyei D . Physicochemical characterisation, molecular docking, and drug-likeness evaluation of hypotensive peptides encrypted in flaxseed proteome. Curr Res Food Sci. 2020; 3:41-50. PMC: 7473365. DOI: 10.1016/j.crfs.2020.03.001. View

10.

Schroder J, Klinger A, Oellien F, Marhofer R, Duszenko M, Selzer P . Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach. J Med Chem. 2013; 56(4):1478-90. DOI: 10.1021/jm3013932. View

11.

Nehar S, Mishra M, Heese K . Identification and characterisation of the novel amyloid-beta peptide-induced protein p17. FEBS Lett. 2009; 583(19):3247-53. DOI: 10.1016/j.febslet.2009.09.018. View

12.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2018; 47(D1):D1102-D1109. PMC: 6324075. DOI: 10.1093/nar/gky1033. View

13.

Lomb L, Barends T, Kassemeyer S, Aquila A, Epp S, Erk B . Radiation damage in protein serial femtosecond crystallography using an x-ray free-electron laser. Phys Rev B Condens Matter Mater Phys. 2013; 84(21):214111. PMC: 3786679. DOI: 10.1103/PhysRevB.84.214111. View

14.

Krieger E, Joo K, Lee J, Lee J, Raman S, Thompson J . Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins. 2009; 77 Suppl 9:114-22. PMC: 2922016. DOI: 10.1002/prot.22570. View

15.

Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X . PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017; 45(W1):W356-W360. PMC: 5793840. DOI: 10.1093/nar/gkx374. View

16.

Xu K, Shi H, Du Y, Ou J . Withaferin A inhibits proliferation of human endometrial cancer cells via transforming growth factor-β (TGF-β) signalling. 3 Biotech. 2021; 11(7):323. PMC: 8192617. DOI: 10.1007/s13205-021-02878-6. View

17.

Schormann N, Ricciardi R, Chattopadhyay D . Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes. Protein Sci. 2014; 23(12):1667-85. PMC: 4253808. DOI: 10.1002/pro.2554. View

18.

Pramanik S, Thaker M, Perumal A, Ekambaram R, Poondla N, Schmidt M . Proteomic Atomics Reveals a Distinctive Uracil-5-Methyltransferase. Mol Inform. 2020; 39(5):e1900135. DOI: 10.1002/minf.201900135. View

19.

Webb B, Sali A . Protein structure modeling with MODELLER. Methods Mol Biol. 2014; 1137:1-15. DOI: 10.1007/978-1-4939-0366-5_1. View

20.

Yang J, Roy A, Zhang Y . BioLiP: a semi-manually curated database for biologically relevant ligand-protein interactions. Nucleic Acids Res. 2012; 41(Database issue):D1096-103. PMC: 3531193. DOI: 10.1093/nar/gks966. View