Molecular Dynamics Approach to Identification of New OGG1 Cancer-Associated Somatic Variants with Impaired Activity | Sciact - CRIS-system of Boreskov Institute of Catalysis

Molecular Dynamics Approach to Identification of New OGG1 Cancer-Associated Somatic Variants with Impaired Activity Full article

Journal

Journal of Biological Chemistry
ISSN: 0021-9258 , E-ISSN: 1083-351X

Output data

Year: 2021, Volume: 296, Article number : 100229, Pages count : 13 DOI: 10.1074/jbc.ra120.014455

Tags

DNA damage; DNA repair; DNA glycosylases; OGG1; genetic polymorphism; personalized medicine; protein function prediction; structure–function; molecular dynamics

Authors

Popov Aleksandr V. ¹ , Endutkin Anton V. ¹ , Yatsenko Darya D. ^2,1 , Yudkina Anna V. ¹ , Barmatov Alexander E. ¹ , Makasheva Kristina A. ² , Raspopova Darya Yu. ² , Diatlova Evgeniia A. ¹ , Zharkov Dmitry O. ^2,1

Affiliations

1	Laboratory of Genome and Protein Engineering, SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russia
2	Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia

DNA of living cells is always exposed to damaging factors. To counteract the consequences of DNA lesions, cells have evolved several DNA repair systems, among which base excision repair is one of the most important systems. Many currently used antitumor drugs act by damaging DNA, and DNA repair often interferes with chemotherapy and radiotherapy in cancer cells. Tumors are usually extremely genetically heterogeneous, often bearing mutations in DNA repair genes. Thus, knowledge of the functionality of cancer-related variants of proteins involved in DNA damage response and repair is of great interest for personalization of cancer therapy. Although computational methods to predict the variant functionality have attracted much attention, at present, they are mostly based on sequence conservation and make little use of modern capabilities in computational analysis of 3D protein structures. We have used molecular dynamics (MD) to model the structures of 20 clinically observed variants of a DNA repair enzyme, 8-oxoguanine DNA glycosylase. In parallel, we have experimentally characterized the activity, thermostability, and DNA binding in a subset of these mutant proteins. Among the analyzed variants of 8-oxoguanine DNA glycosylase, three (I145M, G202C, and V267M) were significantly functionally impaired and were successfully predicted by MD. Alone or in combination with sequence-based methods, MD may be an important functional prediction tool for cancer-related protein variants of unknown significance.

Popov A.V. , Endutkin A.V. , Yatsenko D.D. , Yudkina A.V. , Barmatov A.E. , Makasheva K.A. , Raspopova D.Y. , Diatlova E.A. , Zharkov D.O.
Molecular Dynamics Approach to Identification of New OGG1 Cancer-Associated Somatic Variants with Impaired Activity
Journal of Biological Chemistry. 2021. V.296. 100229 :1-13. DOI: 10.1074/jbc.ra120.014455 WOS Scopus ANCAN PMID OpenAlex

Submitted:	May 19, 2020
Accepted:	Dec 22, 2020
Published print:	Jan 7, 2021
Published online:	Jan 7, 2021

Web of science:	WOS:000672866400207
Scopus:	2-s2.0-85102809499
Chemical Abstracts:	2021:334211
Chemical Abstracts (print):	174:747384
PMID:	33361155
OpenAlex:	W3114269557

DB	Citing
OpenAlex	9
Web of science	5
Scopus	7