vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2020-17-2-211-220vestim-677Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEБиохимические особенности геноварианта 1а2 парвовируса B19, доминирующего во время подъемов заболеваемости в БеларусиBiochemical features of parvovirus B19 genovariant 1a2 dominating during the incidence rise in BelarusЕрмоловичМ. А.YermalovichM. A.

Ермолович Марина Анатольевна – канд. мед. наук, вед. науч. сотрудник

ул. Филимонова, 23, 220114, г. Минск

Marina A. Yermalovich – Ph. D. (Med.), Leading researcher

23, Filimonov Str., 220114, Minsk

yermalovich@mail.ruХрусталевВ. В.KhrustalevV. V.

Хрусталев Владислав Викторович – канд. биол. наук, доцент, заведующий кафедрой

пр. Дзержинского, 83, 220116, г. Минск

Vladislav V. Khrustalev – Ph. D. (Biol.), Associate Professor, Head of the Department

83, Dzerzhinski Ave., 220116, Minsk

vvkhrustalev@mail.ruХрусталеваТ. А.KhrustalevaT. A.

Хрусталева Татьяна Александровна – канд. биол. наук, ст. науч. сотрудник

ул. Академическая, 28, 220072, г. Минск

Tatyana A. Khrustaleva – Ph. D. (Biol.), Senior researcher

28, Akademicheskaya Str., 220072, Minsk

tanissia.lir@gmail.comПобойневВ. В.PoboinevV. V.

Побойнев Виктор Витольдович – магистр мед. наук, аспирант

пр. Дзержинского, 83, 220116, г. Минск

Victor V. Poboinev – Master of Med. Sci., Postgraduate student

83, Dzerzhinski Ave., 220116, Minsk

dremozzew@mail.ruСамойловичЕ. О.SamoilovichE. O.

Самойлович Елена Олеговна – д-р мед. наук, профессор, заведующий лабораторией

ул. Филимонова, 23, 220114, г. Минск

Elena O. Samoilovich – D. Sc. (Med.), Professor, Head of the Laboratory

23, Filimonov Str., 220114, Minsk

esamoilovich@gmail.comРеспубликанский научно-практический центр эпидемиологии и микробиологииRepublican Research and Practical Center for Epidemiology and MicrobiologyБелорусский государственный медицинский университетBelarusian State Medical UniversityИнститут физиологии НАН БеларусиInstitute of Physiology of the National Academy of Sciences of Belarus202005062020172211220Copyright © Ермолович М.А., Хрусталев В.В., Хрусталева Т.А., Побойнев В.В., Самойлович Е.О., 20202020Ермолович М.А., Хрусталев В.В., Хрусталева Т.А., Побойнев В.В., Самойлович Е.О.Yermalovich M.A., Khrustalev V.V., Khrustaleva T.A., Poboinev V.V., Samoilovich E.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/677

Среди штаммов парвовируса человека В19 (В19Р) субгенотипа 1а известно два геноварианта – 1а1, 1а2, из которых преимущественное распространение в период подъема заболеваемости в Беларуси получил 1а2. Целью данного исследования являлся сравнительный анализ аминокислотной изменчивости и направления мутационного давления в разных участках генома штаммов В19Р, относящихся к геновариантам 1а1 и 1а2.

Результаты изучения консенсусных аминокислотных последовательностей геновариантов В19Р и моделей трехмерного строения фрагментов белков показали, что в области главного неструктурного белка NS1 у геноварианта 1а2 имеются две уникальные аминокислотные замены – I181M и E114G, одна из которых (E114G) находится в непосредственной близости к ДНК-связывающему домену, ответственному за прикрепление к участку начала репликации (OBD), и может влиять на скорость репликации и транскрипции вируса. В структурном полипептиде VP геноварианта 1а2 найдено три уникальные аминокислотные замены: V30L, S98N, N533S. Две из них располагаются в наиболее иммуногенном фрагменте VP1u, что позволяет геноварианту 1а2 уходить от иммунного ответа. Изучение направления мутационного давления выявило снижение частоты возникновения трансверсий G на T во второй рамке считывания у геноварианта 1а2, что отражает более высокую скорость транскрипции вследствие аминокислотной замены в белке OBD.

Выявленные различия в структуре антигенных сайтов и системе репликации и транскрипции между различными геновариантами В19Р субгенотипа 1а могут обеспечить повышенный «фитнес» геноварианта 1а2 и его преимущественное распространение в период подъема заболеваемости.

Two genovariants (1a1 and 1a2) are distinguished among Human parvovirus B19 (B19P) of subgenotype 1a, of which 1a2 was predominantly distributed during the incidence rise in Belarus. The aim of this study was a comparative analysis of the amino acid variability and of the mutational pressure directions in different parts of the genome between genovariants 1a1 and 1a2.

The analysis of the consensus amino acid sequences of two genovariants and the three-dimensional structure models of protein fragments was carried out. In total, two unique amino acid substitutions in the main non-structural protein NS1 of 1a2 were found (I181M and E114G), one of which E114G is close to the DNA-binding domain (OBD) responsible for attachment to the replication origin site and can affect the rate of virus replication and transcription. Three unique amino acid substitutions were found in the structural polypeptide VP of 1a2: V30L, S98N, and N533S. Two of them are located in the most immunogenic region VP1u and can contribute to the escape from immune response. The investigation of the mutational pressure direction revealed a decrease in the frequency of G to T transversions in the second reading frame of 1a2, which reflects a higher transcription rate as a result of amino acid substitution in the OBD protein.

The differences revealed between the genetic variants of subgenotype 1a B19P both in the antigenic sites and in the replication and transcription system can provide an increased “fitness” for the genetic variant 1a2 and explain its predominant distribution during the incidence rise.

эритропарвовирус приматов 1парвовирус В19геновариантаминокислотная изменчивостьнаправление мутационного давленияprimate erythroparvovirus 1parvovirus B19genovariantamino acid variabilitymutational pressure directionReferencesRationalization and extension of the taxonomy of the family Parvoviridae / S. F. Cotmore [et al.] // ICTV Official Taxonomy: Updates since the 8th Report, code 2013.001a-aaaV / International Committee on Taxonomy of Viruses (ICTV). – Washington, 2013. – 65 р.Cotmore S. F., Agbandje-McKenna M., Chiorini J. A., Gatherer D., Mukha D. V., Pintel D. J., Qiu J., SoderlundVenermo M., Tattersall P., Tijssen P. Rationalization and extension of the taxonomy of the family Parvoviridae. ICTV official taxonomy: Updates since the 8th Report, code 2013.001a-aaaV. International Committee on Taxonomy of Viruses (ICTV). Washington, 2013. 65 р.Heegaard, E. D. Human parvovirus B19 / E. D. Heegaard, K. E. Brown // Clin. Microbiol. Rev. – 2002. - Vol. 15, N 3. – P. 485–505. https://doi.org/10.1128/cmr.15.3.485-505.2002Heegaard E. D., Brown K. E. Human parvovirus B19. Clinical Microbiology Reviews, 2002, vol. 15, no. 3, pp. 485–505. https://doi.org/10.1128/cmr.15.3.485-505.2002Role of capsid proteins in parvoviruses infection / M. Tu [et al.] // Virol. J. – 2015. – Vol. 12, N 1. – Art. 114. https://doi. org/10.1186/s12985-015-0344-yTu M., Liu F., Chen Sh., Wang M., Cheng A. Role of capsid proteins in parvoviruses infection. Virology Journal, 2015, vol. 12, art. 114. https://doi.org/10.1186/s12985-015-0344-yICTV Virus Taxonomy Profile: Parvoviridae. ICTV Report Consortium / S. F. Cotmore [et al.] // J. Gen. Virol. – 2019. – Vol. 100, N 3. – P. 367–368. https://doi.org/10.1099/jgv.0.001212Cotmore S. F., Agbandje-McKenna M., Canuti M., Chiorini J. A., Eis-Hubinger A. M., Hughes J. [et al.]. ICTV Virus Taxonomy Profile: Parvoviridae. ICTV Report Consortium. Journal of General Virology, 2019, vol. 100, no. 3, pp. 367–368. https://doi.org/10.1099/jgv.0.001212The effects of the 11 kDa protein and the putative X protein on the p6 promoter activity of parvovirus B19 in Hela cells / Y. Dong [et al.] // Virus Genes. – 2013. – Vol. 46, N 1. – P. 167–169. https://doi.org/10.1007/s11262-012-0839-1Dong Y., Huang Y., Wang Y., Xu P., Yang Y., Liu K., Tijssen P., Peng J., Li Y. The effects of the 11 kDa protein and the putative X protein on the p6 promoter activity of parvovirus B19 in Hela cells. Virus Genes, 2013, vol. 46, no. 1, pp. 167–169. https://doi.org/10.1007/s11262-012-0839-1Parvovirus B19 genome as a single, two-state replicative and transcriptional unit / F. Bonvicini [et al.] // Virology. – 2006. – Vol. 347, N 2. – P. 447–454. https://doi.org/10.1016/j.virol.2005.12.014Bonvicini F., Filippone C., Delbarba S., Manaresi E., Zerbini M., Musiani M., Gallinella G. Parvovirus B19 genome as a single, two-state replicative and transcriptional unit. Virology, 2006, vol. 347, no. 2, pp. 447–454. https://doi.org/10.1016/j. virol.2005.12.014Functional analysis and quantitative determination of the expression profile of human parvovirus B19 / F. Bonvicini [et al.] // Virology. – 2008. – Vol. 381, N 2. – P. 168–177. https://doi.org/10.1016/j.virol.2008.09.002Bonvicini F., Filippone C., Manaresi E., Zerbini M., Musiani M., Gallinella G. Functional analysis and quantitative determination of the expression profile of human parvovirus B19. Virology, 2008, vol. 381, no. 2, pp. 168–177. https://doi.org/10.1016/j.virol.2008.09.002Molecular and functional analyses of a human parvovirus B19 infectious clone demonstrates essential roles for NS1, VP1, and the 11-kilodalton protein in virus replication and infectivity / N. Zhi [et al.] // J. Virol. – 2006. – Vol. 80, N 12. – P. 5941–5950. https://doi.org/10.1128/JVI.02430-05Zhi N., Mills I. P., Lu J., Wong S., Filippone C., Brown K. E. Molecular and functional analyses of a human parvovirus B19 infectious clone demonstrates essential roles for NS1, VP1, and the 11-kilodalton protein in virus replication and infectivity. Journal of Virology, 2006, vol. 80, no. 12, pp. 5941–5950. https://doi.org/10.1128/JVI.02430-05Human parvovirus B19 nonstructural protein (NS1) induces cell cycle arrest at G(1) phase / E. Morita [et al.] // J. Virol. – 2003. – Vol. 77, N 5. – P. 2915–2921. https://doi.org/10.1128/jvi.77.5.2915-2921.2003Morita E., Nakashima A., Asao H., Sato H., Sugamura K. Human parvovirus B19 nonstructural protein (NS1) induces cell cycle arrest at G(1) phase. Journal of Virology, 2003, vol. 77, no. 5, pp. 2915–2921. https://doi.org/10.1128/jvi.77.5.2915- 2921.2003Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors / Z. Wan [et al.] // J. Clin. Invest. – 2010. – Vol. 120, N 10. – P. 3530–3544. https://doi.org/10.1172/JCI41805Wan Z., Zhi N., Wong S., Keyvanfar K., Liu D., Raghavachari N. [et al.]. Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors. Journal of Clinical Investigation, 2010, vol. 120, no. 10, pp. 3530–3544. https://doi.org/10.1172/JCI41805Kaufmann, B. The structure of human parvovirus B19 / B. Kaufmann, A. A. Simpson, M. G. Rossmann // Proc. Natl. Acad. Sci. U.S.A. – 2004. – Vol. 101, N 32. – P. 11628–11633. https://doi.org/10.1073/pnas.0402992101Kaufmann B., Simpson A. A., Rossmann M. G. The structure of human parvovirus B19. Proceedings of the National Academy of Sciences of the United States of America, 2004, vol. 101, no. 32, pp. 11628–11633. https://doi.org/10.1073/pnas.0402992101The VP1-unique region of parvovirus B19: amino acid variability and antigenic stability / S. Dorsch [et al.] // J. Gen. Virol. – 2001. – Vol. 82, N 1. – P. 191–199. https://doi.org/10.1099/0022-1317-82-1-191Dorsch S., Kaufmann B., Schaible U., Prohaska E., Wolf H., Modrow S. The VP1-unique region of parvovirus B19: amino acid variability and antigenic stability. Journal of General Virology, 2001, vol. 82, no. 1, pp. 191–199. https://doi.org/10.1099/0022-1317-82-1-191Peptides derived from the unique region of B19 parvovirus minor capsid protein elicit neutralizing antibodies in rabbits / S. Anderson [et al.] // Virology. – 1995. – Vol. 206, N 1. – P. 626–632. https://doi.org/10.1016/s0042-6822(95)80079-4Anderson S., Momoeda M., Kawase M., Kajigaya S., Young N. S. Peptides derived from the unique region of B19 parvovirus minor capsid protein elicit neutralizing antibodies in rabbits. Virology, 1995, vol. 206, no. 1, pp. 626–632. https://doi.org/10.1016/s0042-6822(95)80079-4Identification of immunodominant peptide in the parvovirus B19 VP1 unique region able to elicit a longlasting immune response in humans / E. Zuffi [et al.] // Viral Immunol. – 2001. – Vol. 14, N 2. – P. 151–158. https://doi.org/10.1089/088282401750234529Zuffi E., Manaresi E., Gallinella G., Gentilomi G. A., Venturoli S., Zerbini M., Musiani M. Identification of immunodominant peptide in the parvovirus B19 VP1 unique region able to elicit a long-lasting immune response in humans. Viral Immunology, 2001, vol. 14, no. 2, pp. 151–158. https://doi.org/10.1089/088282401750234529A viral phospholipase A2 is required for parvovirus infectivity / Z. Zádori [et al.] // Dev. Cell. – 2001. – Vol. 1, N 2. – P. 291–302. https://doi.org/10.1016/s1534-5807(01)00031-4Zádori Z., Szelei J., Lacoste M. C., Li Y., Gariépy S., Raymond P., Allaire M., Nabi I. R., Tijssen P. A viral phospholipase A2 is required for parvovirus infectivity. Developmental Cell, 2001, vol. 1, pp. 291–302. https://doi.org/10.1016/s1534-5807(01)00031-4VP1u phospholipase activity is critical for infectivity of full-length parvovirus B19 genomic clones / C. Filippone [et al.] // Virology. – 2008. – Vol. 374, N 2. – P. 444–452. https://doi.org/10.1016/j.virol.2008.01.002Filippone C., Zhi N., Wong S., Lu J., Kajigaya S., Gallinella G., Kakkola L., Söderlund-Venermo M., Young N. S., Brown K. E. VP1u phospholipase activity is critical for infectivity of full-length parvovirus B19 genomic clones. Virology, 2008, vol. 374, no. 2, pp. 444–452. https://doi.org/10.1016/j.virol.2008.01.002The determinants for the enzyme activity of human parvovirus B19 phospholipase A2 (PLA2) and its influence on cultured cells / X. Deng [et al.] // PLoS ONE. – 2013. – Vol. 8, N 4. – P. e61440. https://doi.org/10.1371/journal.pone.0061440Deng X., Dong Y., Yi Q., Huang Y., Zhao D., Yang Y., Tijssen P., Qiu J., Liu K., Li Y. The determinants for the enzyme activity of human parvovirus B19 phospholipase A2 (PLA2) and its influence on cultured cells. PLoS ONE, 2013, vol. 8, no. 4, p. e61440. https://doi.org/10.1371/journal.pone.0061440Visualization of the externalized VP2 N termini of infectious human parvovirus B19 / B. Kaufmann [et al.] // J. Virol. – 2008. – Vol. 82, N 15. – P. 7306–7312. https://doi.org/10.1128/JVI.00512-08Kaufmann B., Chipman P. R., Kostyuchenko V. A., Modrow S., Rossmann M. G. Visualization of the externalized VP2 N termini of infectious human parvovirus B19. Journal of Virology, 2008, vol. 82, no. 15, pp. 7306–7312. https://doi.org/10.1128/JVI.00512-08Genetic diversity within human erythroviruses: identification of three genotypes / A. Servant [et al.] // J. Virol. – 2002. – Vol. 76, N 18. – P. 9124–9134. https://doi.org/10.1128/jvi.76.18.9124-9134.2002Servant A., Laperche S., Lallemand F., Marinho V., De Saint Maur G., Meritet J. F., Garbarg-Chenon A. Genetic diversity within human erythroviruses: identification of three genotypes. Journal of Virology, 2002, vol. 76, no. 18, pp. 9124– 9134. https://doi.org/10.1128/jvi.76.18.9124-9134.2002Phylogenetic analysis of human parvovirus B19, indicating two subgroups of genotype 1 in Vietnamese patients / N. L. Toan [et al.] // J. Gen. Virol. – 2006. – Vol. 87, N 10. – P. 2941–2949. https://doi.org/10.1099/vir.0.82037-0Toan N. L., Duechting A., Kremsner P. G., Song L. H., Ebinger M., Aberle S. [et al.]. Phylogenetic analysis of human parvovirus B19, indicating two subgroups of genotype 1 in Vietnamese patients. Journal of General Virology, 2006, vol. 87, no. 10, pp. 2941–2949. https://doi.org/10.1099/vir.0.82037-0Identification and genetic diversity of two human parvovirus B19 genotype 3 subtypes / A. Parsyan [et al.] // J. Gen. Virol. – 2007. – Vol. 88, N 2. – P. 428–431. https://doi.org/10.1099/vir.0.82496-0Parsyan A., Szmaragd C., Allain J.-P., Candotti D. Identification and genetic diversity of two human parvovirus B19 genotype 3 subtypes. Journal of General Virology, 2007, vol. 88, no. 2, pp. 428–431. https://doi.org/10.1099/vir.0.82496-0Insights into epidemiology of human parvovirus B19 and detection of an unusual genotype 2 variant, Bulgaria, 2004 to 2013 / S. K. Ivanova [et al.] // Eurosurveill. – 2016. – Vol. 21, N 4. – Pii 30116. https://doi.org/10.2807/1560-7917. ES.2016.21.4.30116Ivanova S. K., Mihneva Z. G., Toshev A. K., Kovaleva V. P., Andonova L. G., Muller C. P., Hübschen J. M. Insights into epidemiology of human parvovirus B19 and detection of an unusual genotype 2 variant, Bulgaria, 2004 to 2013. Eurosurveillance, 2016, vol. 21, no. 4, pii 30116. https://doi.org/10.2807/1560-7917.ES.2016.21.4.30116Global co-existence of two evolutionary lineages of parvovirus B19 1a, different in genome-wide synonymous positions / M. W. A. Molenaar-de Backer [et al.] // PLoS ONE. – 2012. – Vol. 7, N 8. – P. e43206. https://doi.org/10.1371/journal.pone.0043206Molenaar-de Backer M. W. A., Lukashov V. V., van Binnendijk R. S., Boot H. J., Zaaijer H. L. Global co-existence of two evolutionary lineages of parvovirus B19 1a, different in genome-wide synonymous positions. PLoS ONE, 2012, vol. 7, no. 8, p. e43206. https://doi.org/10.1371/journal.pone.0043206Molecular and phylogenetic analyses of human parvovirus B19 isolated from Brazilian patients with sickle cell disease and β-thalassemia major and healthy blood donors / S. N. Slavov [et al.] // J. Med. Virol. – 2012. – Vol. 84, N 10. – P. 1652–1665. https://doi.org/10.1002/jmv.23358Slavov S. N., Haddad S. K., Silva-Pinto A. C., Amarilla A. A., Alfonso H. L., Aquino V. H., Covas D. T. Molecular and phylogenetic analyses of human parvovirus B19 isolated from Brazilian patients with sickle cell disease and β-thalassemia major and healthy blood donors. Journal of Medical Virology, 2012, vol. 84, no. 10, pp. 1652–1665. https://doi.org/10.1002/jmv.23358Human parvovirus B19 surveillance in patients with rash and fever from Belarus / M. A. Yermalovich [et al.] // J. Med. Virol. – 2012. – Vol. 84, N 6. – P. 973–978. https://doi.org/10.1002/jmv.23294Yermalovich M. A., Hübschen J. M., Semeiko G. V., Samoilovich E. O., Muller C. P. Human parvovirus B19 surveillance in patients with rash and fever from Belarus. Journal of Medical Virology, 2012, vol. 84, no. 6, pp. 973–978. https://doi.org/10.1002/jmv.23294Ермолович, М. А. Генетические варианты парвовируса B19, циркулирующие в Беларуси в течение эпидемического цикла инфекции, 2005–2016 годы / М. А. Ермолович, Г. В. Семейко, Е. О. Самойлович // Bес. Нац. акад. Беларусi. Сер. мед. навук. – 2019. – Т. 16, № 1. – С. 35–45.Ermolovich M. A., Semeiko G. V., Samoilovich E. O. Genetic variants of parvovirus B19 circulating in Belarus during the epidemic cycle of infection (2005–2016). Vestsi Natsyyanal’nai akademii navuk Belarusi. Seriya meditsinskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2019, vol. 16, no. 1, pp. 35–45 (in Russian).Swiss-model: homology modelling of protein structures and complexes / A. Waterhouse [et al.] // Nucl. Acids Res. – 2018. – Vol. 46, N W1. – P. W296–W303. https://doi.org/10.1093/nar/gky427Waterhouse A., Bertoni M., Bienert S., Studer G., Tauriello G., Gumienny R. [et al.]. Swiss-model: homology modelling of protein structures and complexes. Nucleic Acids Research, 2018, vol. 46, no. W1, pp. W296–W303. https://doi.org/10.1093/nar/gky427Hwang, S. DP-Bind: a web server for sequence-based prediction of DNA-binding residues in DNA-binding proteins / S. Hwang, Z. Gou, I. B. Kuznetsov // Bioinformatics. – 2007. – Vol. 23, N 5. – P. 634–636. https://doi.org/10.1093/bioinformatics/btl672Hwang S., Gou Z., Kuznetsov I. B. DP-Bind: a web server for sequence-based prediction of DNA-binding residues in DNA-binding proteins. Bioinformatics, 2007, vol. 23, no. 5, pp. 634–636. https://doi.org/10.1093/bioinformatics/btl672Transcription-associated mutational pressure in the parvovirus B19 genome: reactivated genomes contribute to the variability of viral populations / V. V. Khrustalev [et al.] // J. Theor. Biol. – 2017. – Vol. 435. – P. 199–207. https://doi.org/10.1016/j.jtbi.2017.09.019Khrustalev V. V., Ermalovich M. A., Hübschen J. M., Khrustaleva T. A. Transcription-associated mutational pressure in the parvovirus B19 genome: reactivated genomes contribute to the variability of viral populations. Journal of Theoretical Biology, 2017, vol. 435, pp. 199–207. https://doi.org/10.1016/j.jtbi.2017.09.019Khrustalev, V. V. Amino acid content of beta strands and alpha helices depends on their flanking secondary structure elements / V. V. Khrustalev, T. A. Khrustaleva, V. V. Poboinev // Biosystems. – 2018. – Vol. 168. – P. 45–54. https://doi.org/10.1016/j.biosystems.2018.04.002Khrustalev V. V., Khrustaleva T. A., Poboinev V. V. Amino acid content of beta strands and alpha helices depends on their flanking secondary structure elements. Biosystems, 2018, vol. 168, pp. 45–54. https://doi.org/10.1016/j.biosystems.2018.04.002Structural studies of AAV2 Rep68 reveal a partially structured linker and compact domain conformation / F. N. Musayev [et al.] // Biochemistry. – 2015. – Vol. 54, N 38. – P. 5907–5919. https://doi.org/10.1021/acs.biochem.5b00610Musayev F. N., Zarate-Perez F., Bardelli M., Bishop C., Saniev E. F., Linden R. M., Henckaerts E., Escalante C. R. Structural studies of AAV2 Rep68 reveal a partially structured linker and compact domain conformation. Biochemistry, 2015, vol. 54, no. 38, pp. 5907–5919. https://doi.org/10.1021/acs.biochem.5b00610Gros, L. Enzymology of the repair of free radicals-induced DNA damage / L. Gros, M. K. Saparbaev, J. Laval // Oncogene. – 2002. – Vol. 21, N 58. – P. 8905–8925. https://doi.org/10.1038/sj.onc.1206005Gros L., Saparbaev M. K., Laval J. Enzymology of the repair of free radicals-induced DNA damage. Oncogene, 2002, vol. 21, no. 58, pp. 8905–8925. https://doi.org/10.1038/sj.onc.1206005Control of adeno-associated virus type 2 cap gene expression: relative influence of helper virus, terminal repeats, and rep proteins / S. Weger [et al.] // J. Virol. – 1997. – Vol. 71, N 11. – P. 8437–8447. https://doi.org/10.1128/jvi.71.11.8437-8447.1997Weger S., Wistuba A., Grimm D., Kleinschmidt J. A. Control of adeno-associated virus type 2 cap gene expression: relative influence of helper virus, terminal repeats, and rep proteins. Journal of Virology, 1997, vol. 71, no. 11, pp. 8437–8447. https://doi.org/10.1128/jvi.71.11.8437-8447.1997The adeno-associated virus type 2 regulatory proteins rep78 and rep68 interact with the transcriptional coactivator PC4 / S. Weger [et al.] // J. Virol. – 1999. – Vol. 73, N 1. – P. 260–269. https://doi.org/10.1128/jvi.73.1.260-269.1999Weger S., Wendland M., Kleinschmidt J. A., Heilbronn R. The adeno-associated virus type 2 regulatory proteins rep78 and rep68 interact with the transcriptional coactivator PC4. Journal of Virology, 1999, vol. 73, no. 1, pp. 260–269. https://doi.org/10.1128/jvi.73.1.260-269.1999Nonstructural protein of parvoviruses B19 and minute virus of mice controls transcription / C. Doerig [et al.] // J. Virol. – 1990. – Vol. 64, N 1. – P. 387–396. https://doi.org/10.1128/jvi.64.1.387-396.1990Doerig C., Hirt B., Antonietti J. P., Beard P. Nonstructural protein of parvoviruses B19 and minute virus of mice controls transcription. Journal of Virology, 1990, vol. 64, no. 1, pp. 387–396. https://doi.org/10.1128/jvi.64.1.387-396.1990NS1 protein of parvovirus B19 interacts directly with DNA sequences of the P6 promoter and with the cellular transcription factors Sp1/Sp3 / U. Raab [et al.] // Virology. – 2002. – Vol. 293, N 1. – P. 86–93. https://doi.org/10.1006/viro.2001.1285Raab U., Beckenlehner K., Lowin T., Niller H. H., Doyle S., Modrow S. NS1 protein of parvovirus B19 interacts directly with DNA sequences of the P6 promoter and with the cellular transcription factors Sp1/Sp3. Virology, 2002, vol. 293, no. 1, pp. 86–93. https://doi.org/10.1006/viro.2001.1285

The authors declare that there are no conflicts of interest present.