A gene dosage-dependent effect unveils NBS1 as both a haploinsufficient tumour suppressor and an essential gene for SHH-medulloblastoma.

Autor: Petroni M; Department of Molecular Medicine, University La Sapienza, Rome, Italy.; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy., Fabretti F; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Di Giulio S; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Nicolis di Robilant V; Department of Molecular Medicine, University La Sapienza, Rome, Italy., La Monica V; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Moretti M; Department of Experimental Medicine, University La Sapienza, Rome, Italy., Belardinilli F; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Bufalieri F; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Coppa A; Department of Experimental Medicine, University La Sapienza, Rome, Italy., Paci P; Department of Computer Engineering, Automation and Management, University La Sapienza, Rome, Italy.; Institute for Systems Analysis and Computer Science Antonio Ruberti, National Research Council, Rome, Italy., Corsi A; Department of Molecular Medicine, University La Sapienza, Rome, Italy., De Smaele E; Department of Experimental Medicine, University La Sapienza, Rome, Italy., Coni S; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Canettieri G; Department of Molecular Medicine, University La Sapienza, Rome, Italy.; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy., Di Marcotullio L; Department of Molecular Medicine, University La Sapienza, Rome, Italy., Wang ZQ; Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany., Giannini G; Department of Molecular Medicine, University La Sapienza, Rome, Italy.; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
Jazyk: angličtina
Zdroj: Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2022 Oct; Vol. 48 (6), pp. e12837. Date of Electronic Publication: 2022 Aug 10.
DOI: 10.1111/nan.12837
Abstrakt: Aims: Inherited or somatic mutations in the MRE11, RAD50 and NBN genes increase the incidence of tumours, including medulloblastoma (MB). On the other hand, MRE11, RAD50 and NBS1 protein components of the MRN complex are often overexpressed and sometimes essential in cancer. In order to solve the apparent conundrum about the oncosuppressive or oncopromoting role of the MRN complex, we explored the functions of NBS1 in an MB-prone animal model.
Materials and Methods: We generated and analysed the monoallelic or biallelic deletion of the Nbn gene in the context of the SmoA1 transgenic mouse, a Sonic Hedgehog (SHH)-dependent MB-prone animal model. We used normal and tumour tissues from these animal models, primary granule cell progenitors (GCPs) from genetically modified animals and NBS1-depleted primary MB cells, to uncover the effects of NBS1 depletion by RNA-Seq, by biochemical characterisation of the SHH pathway and the DNA damage response (DDR) as well as on the growth and clonogenic properties of GCPs.
Results: We found that monoallelic Nbn deletion increases SmoA1-dependent MB incidence. In addition to a defective DDR, Nbn +/- GCPs show increased clonogenicity compared to Nbn +/+ GCPs, dependent on an enhanced Notch signalling. In contrast, full Nbn KO impairs MB development both in SmoA1 mice and in an SHH-driven tumour allograft.
Conclusions: Our study indicates that Nbn is haploinsufficient for SHH-MB development whereas full Nbn KO is epistatic on SHH-driven MB development, thus revealing a gene dosage-dependent effect of Nbn inactivation on SHH-MB development.
(© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
Databáze: MEDLINE
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