The effect of NBS1 heterozygous inactivating mutation in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis in mice

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

BACKGROUND: The creation of new experimental models carrying various heterozygous inactivating mutations in DNA repair genes and their carcinogenesis studies could expand our understanding of the spectrum of possible neoplasms that patients with such mutations are at risk of developing.

AIM: The study of the effect of NBS1 inactivating heterozygous mutation (с.1971insT, p.Arg658Stop) in a model of 7,12-dimethylbenz[a]anthracene (DMBA) induced carcinogenesis in mice.

MATERIALS AND METHODS: Carcinogenesis was induced in 2-month-old female mice with and without NBS1 heterozygous mutation by intragastric administration of 7,12-DMBA (dose of 50 mg/kg once a week, for 8 weeks) on a high-fat diet. Lifetime observation was conducted, and parameters of lifespan and carcinogenesis were evaluated.

RESULTS: NBS1 inactivating heterozygous mutation had no significant effect on the incidence of tumor pathology induced by 7,12-DMBA, but somewhat accelerated the rate of tumor development and, consequently, the death of animals. The presence of the mutation increased the sensitivity to carcinogen toxic effect, which was expressed in a statistically significant increase in death rate (by 35%) in the early stages of the study. The mean lifespan in female NBS1 mutant mice was reduced by 14% compared to mutation-free animals.

CONCLUSION: Carrying NBS1 inactivating heterozygous mutation (с.1971insT, p.Arg658Stop) worsens the prognosis of survival in the model of chemically induced 7,12-DMBA carcinogenesis in mice.

Full Text

Restricted Access

About the authors

Maria N. Yurova

N.N. Petrov National Medical Research Centre of Oncology

Author for correspondence.
Email: yumarni@gmail.com
ORCID iD: 0000-0003-3589-5871
SPIN-code: 3497-5175

Cand.  Sci. (Bio.)

Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Alexey G. Golubev

N.N. Petrov National Medical Research Centre of Oncology

Email: lxglbv@rambler.ru
ORCID iD: 0000-0002-2129-6205
SPIN-code: 2871-0779

Cand.  Sci. (Bio.)

Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Elena I. Fedoros

N.N. Petrov National Medical Research Centre of Oncology

Email: elenafedoros@gmail.com
ORCID iD: 0000-0002-2426-9843
SPIN-code: 3302-1384

Cand.  Sci. (Bio.)

Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Irina A. Tumanyan

N.N. Petrov National Medical Research Centre of Oncology

Email: itumanyan@mail.ru
ORCID iD: 0000-0002-8926-1519
SPIN-code: 1165-4685
Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Yulia D. Von

N.N. Petrov National Medical Research Centre of Oncology

Email: takeo_yuki@mail.ru
ORCID iD: 0000-0002-5161-5940
SPIN-code: 8621-1112
Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Alexander L. Semenov

N.N. Petrov National Medical Research Centre of Oncology

Email: genesem7@gmail.com
ORCID iD: 0000-0002-5190-0629
SPIN-code: 4301-8679

MD, Cand.  Sci. (Med.)

Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Ekaterina A. Otradnova

N.N. Petrov National Medical Research Centre of Oncology

Email: katya.otradnova@mail.ru
ORCID iD: 0009-0003-0158-1820
SPIN-code: 9861-0730
Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Evgeny N. Imyanitov

N.N. Petrov National Medical Research Centre of Oncology

Email: evgeny@imyanitov.spb.ru
ORCID iD: 0000-0003-4529-7891
SPIN-code: 1909-7323

MD, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences

Russian Federation, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

References

  1. Rahman S, Canny MD, Buschmann TA, et al. A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex. Cells. 2020;9(7):1–25. doi: 10.3390/cells9071678
  2. Belhadj S, Khurram A, Bandlamudi C, et al. NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects. Clinical Cancer Research. 2023;29(2):422–431. doi: 10.1158/1078-0432.CCR-22-1703
  3. Buslov KG, Iyevleva AG, Chekmariova EV, et al. NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia. International Journal of Cancer. 2005;114(4):585–589. doi: 10.1002/IJC.20765
  4. Masi A, Antoccia A. NBS1 Heterozygosity and Cancer Risk. Current Genomics. 2008;9(4):275–281. doi: 10.2174/138920208784533610
  5. Otahalova B, Volkova Z, Soukupova J, et al. Importance of Germline and Somatic Alterations in Human MRE11, RAD50, and NBN Genes Coding for MRN Complex. International Journal of Molecular Sciences. 2023;24(6):5612. doi: 10.3390/IJMS24065612
  6. McPherson MT, Holub AS, Husbands AY, et al. Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells. Cancers. 2020;12(12):1–20. doi: 10.3390/CANCERS12123794
  7. Stracker TH, Petrini JHJ. The MRE11 complex: Starting from the ends. Nature Reviews Molecular Cell Biology. 2011;12(2):90–103. doi: 10.1038/nrm3047
  8. Zhao Y, Tan YS, Aupperlee MD, et al. Pubertal high fat diet: Effects on mammary cancer development. Breast Cancer Research. 2013;15(5):1. doi: 10.1186/bcr3561
  9. Turusov VS, Mohr U, editors. Pathology of Tumours in Laboratory Animals, 2nd Edition, Volume 2: Tumours of the Mouse. IARC; 1990.
  10. Kang J, Bronson RT, Xu Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. The EMBO Journal. 2002;21(6):1447–1455. doi: 10.1093/emboj/21.6.1447
  11. Stracker TH, Morales M, Couto SS, et al. The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex. Nature. 2007;447:218–221. doi: 10.1038/nature05740
  12. Wessendorf P, Vijg J, Nussenzweig A, Digweed M. Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2014;769:11–16. doi: 10.1016/j.mrfmmm.2014.07.001
  13. Kim JH, Grosbart M, Anand R, et al. The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression. Cell Reports. 2017;18(2):496–507. doi: 10.1016/j.celrep.2016.12.035
  14. Yurova MN, Golubev AG, Aleksakhina SN, et al. The effect of inactivating heterozygous mutation in NBS1 gene on DNA damage and repair markers and apoptosis in mice. Bulletin of Experimental Biology and Medicine. 2023;175(2):197–202. (In Russ). doi: 10.47056/0365-9615-2023-175-2-197-202

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Dynamics of body weight in female NBS1 heterozygous mutant mice (BALB/c/F1) in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Data presented as «mean ± standard error of the mean». * — difference is statistically significant, р <0.05; NBS1insT — mutation in NBS1 gene present; wt — wild type.

Download (176KB)
Indexing metadata
3. Fig. 2. Survival curves of female NBS1 heterozygous mutant mice (BALB/c/F1) in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. NBS1insT — mutation in NBS1 gene present; wt — wild type.

Download (120KB)
Indexing metadata
4. Fig. 3. Morphological study of mammary carcinoma sections. a — squamous cell keratinizing carcinoma; b — metastasis to the lung. Hematoxylin-eosin, ×100.

Download (365KB)
Indexing metadata
5. Fig. 4. Morphological study of lymphoma sections. a — lymphoma lesion of the lung; b — lymphoma lesion of the kidney. Hematoxylin-eosin, ×100.

Download (436KB)
Indexing metadata
6. Fig. 5. Mortality curves of female tumor-bearing mice (BALB/c/F1) carrying NBS1 heterozygous mutations in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. NBS1insT — mutation in NBS1 gene present; wt — wild type.

Download (118KB)
Indexing metadata

Copyright (c) 2023 Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 86496 от 11.12.2023 г. 
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ЭЛ № ФС 77 - 80673 от 23.03.2021 г.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies