DNA repair functional analyses of NBN hypomorphic variants associated with NBN-related infertility.
Adult
Ataxia Telangiectasia Mutated Proteins
/ genetics
Cell Cycle Proteins
/ genetics
DNA Mutational Analysis
DNA Repair
Female
Flow Cytometry
Gene Expression Regulation
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genetic Variation
Humans
Infertility
/ diagnosis
Male
Nijmegen Breakage Syndrome
/ diagnosis
Nuclear Proteins
/ genetics
Protein Binding
Signal Transduction
ATM
FHA
NBN
Nijmegen syndrome
cell cycle checkpoint
infertility
premature ovarian failure
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
13
07
2019
revised:
17
10
2019
accepted:
03
11
2019
pubmed:
16
11
2019
medline:
22
7
2021
entrez:
16
11
2019
Statut:
ppublish
Résumé
Nijmegen breakage syndrome caused by biallelic pathogenic variants of the DNA-damage response gene NBN, is characterized by severe microcephaly, cancer proneness, infertility, and karyotype abnormalities. We previously reported NBN variants in siblings suffering from fertility defects. Here, we identify a new founder NBN variant (c.442A>G, p.(Thr148Ala)) in Lebanese patients associated with isolated infertility. Functional analyses explored preserved or altered functions correlated with their remarkably mild phenotype. Transcript and protein analyses supported the use of an alternative transcript with in-frame skipping of exons 4-5, leading to p84-NBN protein with a preserved forkhead-associated (FHA) domain. The level of NBN was dramatically reduced and the MRN complex delocalized to the cytoplasm. Interestingly, ataxia-elangiectasia mutated (ATM) also shifted from the nucleus to the cytoplasm, suggesting some interaction between ATM and the MRN complex at a steady state. The ATM pathway activation, attenuated in typical patients with NBS, appeared normal under camptothecin treatment in these new NBN-related infertile patients. Cell cycle checkpoint defect was present in these atypical patients, although to a lesser extent than in typical patients with NBS. In conclusion, we report three new NBN-related infertile patients and we suggest that preserved FHA domain could be responsible for the mild phenotype and intermediate DNA-damage response defects.
Substances chimiques
Cell Cycle Proteins
0
NBN protein, human
0
Nuclear Proteins
0
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
608-618Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
Anand, R., Ranjha, L., Cannavo, E., & Cejka, P. (2016). Phosphorylated CtIP functions as a co-factor of the MRE11-RAD50-NBS1 endonuclease in DNA end resection. Molecular Cell, 64(5), 940-950. https://doi.org/10.1016/j.molcel.2016.10.017
Barlow, C., Ribaut-Barassin, C., Zwingman, T. A., Pope, A. J., Brown, K. D., Owens, J. W., … Wynshaw-Boris, A. (2000). ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation. Proceedings of the National Academy of Sciences of the United States of America, 97(2), 871-876.
Chrzanowska, K. H., Gregorek, H., Dembowska-Baginska, B., Kalina, M. A., & Digweed, M. (2012). Nijmegen breakage syndrome (NBS). Orphanet Journal of Rare Diseases, 7, 13. https://doi.org/10.1186/1750-1172-7-13
Cilli, D., Mirasole, C., Pennisi, R., Pallotta, V., D'Alessandro, A., Antoccia, A., … di Masi, A. (2014). Identification of the interactors of human nibrin (NBN) and of its 26 kDa and 70 kDa fragments arising from the NBN 657del5 founder mutation. PLoS One, 9(12), https://doi.org/10.1371/journal.pone.0114651. e114651
Difilippantonio, S., Celeste, A., Fernandez-Capetillo, O., Chen, H. T., Reina San Martin, B., Van Laethem, F., … Nussenzweig, A. (2005). Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nature Cell Biology, 7(7), 675-685. https://doi.org/10.1038/ncb1270
Digweed, M., & Sperling, K. (2004). Nijmegen breakage syndrome: Clinical manifestation of defective response to DNA double-strand breaks. DNA Repair, 3(8-9), 1207-1217. https://doi.org/10.1016/j.dnarep.2004.03.004
Dupre, A., Boyer-Chatenet, L., & Gautier, J. (2006). Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex. Nature Structural & Molecular Biology, 13(5), 451-457. https://doi.org/10.1038/nsmb1090
Falck, J., Petrini, J. H., Williams, B. R., Lukas, J., & Bartek, J. (2002). The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genetics, 30(3), 290-294. https://doi.org/10.1038/ng845
Fievet, A., Bellanger, D., Rieunier, G., Dubois d'Enghien, C., Sophie, J., Calvas, P., … Stern, M. H. (2019). Functional classification of ATM variants in ataxia-telangiectasia patients. Human Mutation, 40(10), 1713-1730. https://doi.org/10.1002/humu.23778
Fievet, A., Bellanger, D., Valence, S., Mobuchon, L., Afenjar, A., Giuliano, F., … Stern, M. H. (2019). Three new cases of ataxia-telangiectasia-like disorder: No impairment of the ATM pathway, but S-phase checkpoint defect. Human Mutation, 40(10), 1690-1699. https://doi.org/10.1002/humu.23773
Fievet, A., Bernard, V., Tenreiro, H., Dehainault, C., Girard, E., Deshaies, V., … Houdayer, C. (2019). ART-DeCo: Easy tool for detection and characterization of cross-contamination of DNA samples in diagnostic next-generation sequencing analysis. European Journal of Human Genetics, 27(5), 792-800. https://doi.org/10.1038/s41431-018-0317-x
Frappart, P. O., Tong, W. M., Demuth, I., Radovanovic, I., Herceg, Z., Aguzzi, A., … Wang, Z. Q. (2005). An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nature Medicine, 11(5), 538-544. https://doi.org/10.1038/nm1228
Haince, J. F., McDonald, D., Rodrigue, A., Dery, U., Masson, J. Y., Hendzel, M. J., & Poirier, G. G. (2008). PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. The Journal of Biological Chemistry, 283(2), 1197-1208. https://doi.org/10.1074/jbc.M706734200
Jayaraman, D., Bae, B. I., & Walsh, C. A. (2018). The genetics of primary microcephaly. Annual Review of Genomics and Human Genetics, 19, 177-200. https://doi.org/10.1146/annurev-genom-083117-021441
Lespinasse, J., Hoffmann, P., Lauge, A., Stoppa-Lyonnet, D., Felmann, F., Pons, J. C., & Lesca, G. (2005). Chromosomal instability in two siblings with gonad deficiency: Case report. Human Reproduction, 20(1), 158-162. https://doi.org/10.1093/humrep/deh584
Levy, A., & Lang, A. E. (2018). Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations. Movement Disorders, 33(8), 1238-1247. https://doi.org/10.1002/mds.27319
Li, M., Lu, L. Y., Yang, C. Y., Wang, S., & Yu, X. (2013). The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response. Genes & Development, 27(16), 1752-1768. https://doi.org/10.1101/gad.226357.113
Lloyd, J., Chapman, J. R., Clapperton, J. A., Haire, L. F., Hartsuiker, E., Li, J., … Smerdon, S. J. (2009). A supramodular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA damage. Cell, 139(1), 100-111. https://doi.org/10.1016/j.cell.2009.07.043
Maraschio, P., Peretti, D., Lambiase, S., Lo Curto, F., Caufin, D., Gargantini, L., … Zuffardi, O. (1986). A new chromosome instability disorder. Clinical Genetics, 30(5), 353-365. https://doi.org/10.1111/j.1399-0004.1986.tb01892.x
Maser, R. S., Zinkel, R., & Petrini, J. H. (2001). An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nature Genetics, 27(4), 417-421. https://doi.org/10.1038/86920
Matsumoto, Y., Miyamoto, T., Sakamoto, H., Izumi, H., Nakazawa, Y., Ogi, T., … Matsuura, S. (2011). Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. DNA Repair, 10(3), 314-321. https://doi.org/10.1016/j.dnarep.2010.12.002
Qvist, P., Huertas, P., Jimeno, S., Nyegaard, M., Hassan, M. J., Jackson, S. P., & Borglum, A. D. (2011). CtIP mutations cause Seckel and Jawad syndromes. PLoS Genetics, 7(10), https://doi.org/10.1371/journal.pgen.1002310. e1002310
Schiller, C. B., Lammens, K., Guerini, I., Coordes, B., Feldmann, H., Schlauderer, F., … Hopfner, K. P. (2012). Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling. Nature Structural & Molecular Biology, 19(7), 693-700. https://doi.org/10.1038/nsmb.2323
Seemanova, E., Sperling, K., Neitzel, H., Varon, R., Hadac, J., Butova, O., … Digweed, M. (2005). Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability. Journal of Medical Genetics, 43(3), 218-224. https://doi.org/10.1136/jmg.2005.035287
Stracker, T. H., & Petrini, J. H. (2011). The MRE11 complex: Starting from the ends. Nature Reviews Molecular Cell Biology, 12(2), 90-103. https://doi.org/10.1038/nrm3047
Tucker, E. J., Grover, S. R., Robevska, G., van den Bergen, J., Hanna, C., & Sinclair, A. H. (2018). Identification of variants in pleiotropic genes causing “isolated” premature ovarian insufficiency: Implications for medical practice. European Journal of Human Genetics, 26(9), 1319-1328. https://doi.org/10.1038/s41431-018-0140-4
Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman, L., & Shiloh, Y. (2003). Requirement of the MRN complex for ATM activation by DNA damage. The EMBO Journal, 22(20), 5612-5621. https://doi.org/10.1093/emboj/cdg541
Varon, R., Dutrannoy, V., Weikert, G., Tanzarella, C., Antoccia, A., Stockl, L., … Maraschio, P. (2006). Mild Nijmegen breakage syndrome phenotype due to alternative splicing. Human Molecular Genetics, 15(5), 679-689. https://doi.org/10.1093/hmg/ddi482
Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., … Reis, A. (1998). Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell, 93(3), 467-476. https://doi.org/10.1016/S0092-8674(00)81174-5
Vissinga, C. S., Yeo, T. C., Warren, S., Brawley, J. V., Phillips, J., Cerosaletti, K., & Concannon, P. (2009). Nuclear export of NBN is required for normal cellular responses to radiation. Molecular and Cellular Biology, 29(4), 1000-1006. https://doi.org/10.1128/MCB.01131-08
Warcoin, M., Lespinasse, J., Despouy, G., Dubois d'Enghien, C., Laugé, A., Portnoï, M.-F., … Henri Stern, M. (2009). Fertility defects revealing germline biallelic nonsense NBN mutations. Human Mutation, 30(3), 424-430. https://doi.org/10.1002/humu.20904
Williams, R. S., Dodson, G. E., Limbo, O., Yamada, Y., Williams, J. S., Guenther, G., … Tainer, J. A. (2009). Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair. Cell, 139(1), 87-99. https://doi.org/10.1016/j.cell.2009.07.033
Zhang, Y., Lim, C. U., Zhou, J., & Liber, H. H. (2007). The effects of NBS1 knockdown by small interfering RNA on the ionizing radiation-induced apoptosis in human lymphoblastoid cells with different p53 status. Toxicology Letters, 171(1-2), 50-59. https://doi.org/10.1016/j.toxlet.2007.04.006
Zhu, J., Petersen, S., Tessarollo, L., & Nussenzweig, A. (2001). Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Current Biology, 11(2), 105-109. https://doi.org/10.1016/S0960-9822(01)00019-7