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BRG1 loss predisposes lung cancers to replicative stress and ATR dependency
dc.contributor.author | Gupta, Manav | |
dc.contributor.author | Concepcion, Carla P | |
dc.contributor.author | Fahey, Caroline G | |
dc.contributor.author | Keshishian, Hasmik | |
dc.contributor.author | Bhutkar, Arjun | |
dc.contributor.author | Brainson, Christine F | |
dc.contributor.author | Sanchez-Rivera, Francisco J | |
dc.contributor.author | Pessina, Patrizia | |
dc.contributor.author | Kim, Jonathan Y | |
dc.contributor.author | Simoneau, Antoine | |
dc.contributor.author | Paschini, Margherita | |
dc.contributor.author | Beytagh, Mary C | |
dc.contributor.author | Stanclift, Caroline R | |
dc.contributor.author | Schenone, Monica | |
dc.contributor.author | Mani, DR | |
dc.contributor.author | Li, Chendi | |
dc.contributor.author | Oh, Audris | |
dc.contributor.author | Li, Fei | |
dc.contributor.author | Hu, Hai | |
dc.contributor.author | Karatza, Angeliki | |
dc.contributor.author | Bronson, Roderick T | |
dc.contributor.author | Shaw, Alice T | |
dc.contributor.author | Hata, Aaron N | |
dc.contributor.author | Wong, Kwok-Kin | |
dc.contributor.author | Zou, Lee | |
dc.contributor.author | Carr, Steven A | |
dc.contributor.author | Jacks, Tyler | |
dc.contributor.author | Kim, Carla F | |
dc.date.accessioned | 2021-10-27T19:53:00Z | |
dc.date.available | 2021-10-27T19:53:00Z | |
dc.date.issued | 2020 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/133470 | |
dc.description.abstract | Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. | |
dc.language.iso | en | |
dc.publisher | American Association for Cancer Research (AACR) | |
dc.relation.isversionof | 10.1158/0008-5472.CAN-20-1744 | |
dc.rights | Creative Commons Attribution-Noncommercial-Share Alike | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | |
dc.source | PMC | |
dc.title | BRG1 loss predisposes lung cancers to replicative stress and ATR dependency | |
dc.type | Article | |
dc.relation.journal | Cancer Research | |
dc.eprint.version | Author's final manuscript | |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | |
eprint.status | http://purl.org/eprint/status/PeerReviewed | |
dc.date.updated | 2021-07-16T18:16:35Z | |
dspace.orderedauthors | Gupta, M; Concepcion, CP; Fahey, CG; Keshishian, H; Bhutkar, A; Brainson, CF; Sanchez-Rivera, FJ; Pessina, P; Kim, JY; Simoneau, A; Paschini, M; Beytagh, MC; Stanclift, CR; Schenone, M; Mani, DR; Li, C; Oh, A; Li, F; Hu, H; Karatza, A; Bronson, RT; Shaw, AT; Hata, AN; Wong, K-K; Zou, L; Carr, SA; Jacks, T; Kim, CF | |
dspace.date.submission | 2021-07-16T18:16:38Z | |
mit.journal.volume | 80 | |
mit.journal.issue | 18 | |
mit.license | OPEN_ACCESS_POLICY | |
mit.metadata.status | Authority Work and Publication Information Needed |