Cargando…

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

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 ofte...

Descripción completa

Detalles Bibliográficos
Autores principales: Popov, Aleksandr V., Endutkin, Anton V., Yatsenko, Darya D., Yudkina, Anna V., Barmatov, Alexander E., Makasheva, Kristina A., Raspopova, Darya Yu., Diatlova, Evgeniia A., Zharkov, Dmitry O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948927/
https://www.ncbi.nlm.nih.gov/pubmed/33361155
http://dx.doi.org/10.1074/jbc.RA120.014455
_version_ 1783663457809203200
author Popov, Aleksandr V.
Endutkin, Anton V.
Yatsenko, Darya D.
Yudkina, Anna V.
Barmatov, Alexander E.
Makasheva, Kristina A.
Raspopova, Darya Yu.
Diatlova, Evgeniia A.
Zharkov, Dmitry O.
author_facet Popov, Aleksandr V.
Endutkin, Anton V.
Yatsenko, Darya D.
Yudkina, Anna V.
Barmatov, Alexander E.
Makasheva, Kristina A.
Raspopova, Darya Yu.
Diatlova, Evgeniia A.
Zharkov, Dmitry O.
author_sort Popov, Aleksandr V.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7948927
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-79489272021-03-19 Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity Popov, Aleksandr V. Endutkin, Anton V. Yatsenko, Darya D. Yudkina, Anna V. Barmatov, Alexander E. Makasheva, Kristina A. Raspopova, Darya Yu. Diatlova, Evgeniia A. Zharkov, Dmitry O. J Biol Chem Research Article 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. American Society for Biochemistry and Molecular Biology 2021-01-07 /pmc/articles/PMC7948927/ /pubmed/33361155 http://dx.doi.org/10.1074/jbc.RA120.014455 Text en © 2021 THE AUTHORS https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Popov, Aleksandr V.
Endutkin, Anton V.
Yatsenko, Darya D.
Yudkina, Anna V.
Barmatov, Alexander E.
Makasheva, Kristina A.
Raspopova, Darya Yu.
Diatlova, Evgeniia A.
Zharkov, Dmitry O.
Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title_full Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title_fullStr Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title_full_unstemmed Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title_short Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
title_sort molecular dynamics approach to identification of new ogg1 cancer-associated somatic variants with impaired activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948927/
https://www.ncbi.nlm.nih.gov/pubmed/33361155
http://dx.doi.org/10.1074/jbc.RA120.014455
work_keys_str_mv AT popovaleksandrv moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT endutkinantonv moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT yatsenkodaryad moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT yudkinaannav moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT barmatovalexandere moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT makashevakristinaa moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT raspopovadaryayu moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT diatlovaevgeniiaa moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity
AT zharkovdmitryo moleculardynamicsapproachtoidentificationofnewogg1cancerassociatedsomaticvariantswithimpairedactivity