TY - JOUR

T1 - Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity

AU - Popov, Aleksandr V.

AU - Endutkin, Anton V.

AU - Yatsenko, Darya D.

AU - Yudkina, Anna V.

AU - Barmatov, Alexander E.

AU - Makasheva, Kristina A.

AU - Raspopova, Darya Yu

AU - Diatlova, Evgeniia A.

AU - Zharkov, Dmitry O.

N1 - Funding Information: Acknowledgments—DNA sequencing was performed at the SB RAS Genomics Core Facility. MD simulations were performed at the Supercomputing center of the Novosibirsk State University. Partial salary support from the Russian Ministry of Science and Higher Education (state funded budget projects АААА-А17-117020210023-1 and FSUS-2020-0035) is acknowledged. Funding Information: by the Russian Foundation for Basic Research (grant 17-00-00261/ Funding Information: 17-00-00265-komfi to D. O. Z) and Russian Science Foundation (grant 18-74-00052 to A. V. P.). Publisher Copyright: © 2021 THE AUTHORS. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85102809499&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA120.014455

DO - 10.1074/jbc.RA120.014455

M3 - Article

C2 - 33361155

AN - SCOPUS:85102809499

VL - 296

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

M1 - 100229

ER -