A gene dosage-dependent effect unveils NBS1 as both a haploinsufficient tumour suppressor and an essential gene for SHH-medulloblastoma.
MRN complex
Nijmegen breakage syndrome
Notch
Sonic Hedgehog
haploinsufficiency
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
10
05
2022
received:
07
03
2022
accepted:
05
07
2022
pubmed:
16
7
2022
medline:
9
9
2022
entrez:
15
7
2022
Statut:
ppublish
Résumé
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. 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. We found that monoallelic Nbn deletion increases SmoA1-dependent MB incidence. In addition to a defective DDR, Nbn Our study indicates that Nbn is haploinsufficient for SHH-MB development whereas full Nbn
Identifiants
pubmed: 35839783
doi: 10.1111/nan.12837
pmc: PMC9542137
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
Hedgehog Proteins
0
Nijmegen breakage syndrome 1 protein, mouse
0
Shh protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12837Informations de copyright
© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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