Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma
dc.contributor.author | Tamayo-Orrego, Lukas | |
dc.contributor.author | Gallo, David | |
dc.contributor.author | Racicot, Frédéric | |
dc.contributor.author | Bemmo, Amandine | |
dc.contributor.author | Mohan, Sushmetha | |
dc.contributor.author | Ho, Brandon | |
dc.contributor.author | Salameh, Samer | |
dc.contributor.author | Hoang, Trang | |
dc.contributor.author | Jackson, Andrew P. | |
dc.contributor.author | Brown, Grant W. | |
dc.contributor.author | Charron, Frédéric | |
dc.date.accessioned | 2021-11-15T15:37:14Z | |
dc.date.available | MONTHS_WITHHELD:6 | fr |
dc.date.available | 2021-11-15T15:37:14Z | |
dc.date.issued | 2020-07-20 | |
dc.identifier.uri | http://hdl.handle.net/1866/25802 | |
dc.publisher | Nature Research | fr |
dc.subject | Cancer | fr |
dc.subject | Cancer models | fr |
dc.subject | CNS cancer | fr |
dc.subject | Homologous recombination | fr |
dc.subject | Origin firing | fr |
dc.title | Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma | fr |
dc.type | Article | fr |
dc.contributor.affiliation | Université de Montréal. Faculté de médecine. Département de médecine | fr |
dc.identifier.doi | 10.1038/s43018-020-0094-7 | |
dcterms.abstract | The mechanisms generating cancer-initiating mutations are not well understood. Sonic hedgehog (SHH) pathway activation is frequent in medulloblastoma (MB), with PTCH1 mutations being a common initiating event. Here we investigated the role of the developmental mitogen SHH in initiating carcinogenesis in the cells of origin: granule cell progenitors (GCPs). We delineate a molecular mechanism for tumor initiation in MB. Exposure of GCPs to Shh causes a distinct form of DNA replication stress, increasing both origin firing and fork velocity. Shh promotes DNA helicase loading and activation, with increased Cdc7-dependent origin firing. The S-phase duration is reduced and hyper-recombination occurs, causing copy number neutral loss of heterozygosity—a frequent event at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing reduces recombination and preneoplastic tumor formation in mice. Therefore, tissue-specific replication stress induced by Shh promotes loss of heterozygosity, which in tumor-prone Ptch1+/− GCPs results in loss of this tumor suppressor—an early cancer-initiating event. | fr |
dcterms.isPartOf | urn:ISSN:2662-1347 | fr |
dcterms.language | eng | fr |
UdeM.ReferenceFournieParDeposant | Tamayo-Orrego, L., Gallo, D., Racicot, F. et al. Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma. Nat Cancer 1, 840–854 (2020). https://doi.org/10.1038/s43018-020-0094-7 DOI https://doi.org/10.1038/s43018-020-0094-7 | fr |
UdeM.VersionRioxx | Version acceptée / Accepted Manuscript | fr |
oaire.citationTitle | Nature cancer | fr |
oaire.citationVolume | 1 | fr |
oaire.citationStartPage | 840 | fr |
oaire.citationEndPage | 854 | fr |
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