dc.contributor.author | Feng, H | |
dc.contributor.author | Lane, KA | |
dc.contributor.author | Roumeliotis, TI | |
dc.contributor.author | Jeggo, PA | |
dc.contributor.author | Somaiah, N | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Downs, JA | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2022-08-24T11:57:14Z | |
dc.date.available | 2022-08-24T11:57:14Z | |
dc.date.issued | 2022-07-28 | |
dc.identifier | gad.349249.121 | |
dc.identifier.citation | Genes and Development, 2022, | |
dc.identifier.issn | 0890-9369 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5321 | |
dc.identifier.eissn | 1549-5477 | |
dc.identifier.eissn | 1549-5477 | |
dc.identifier.doi | 10.1101/gad.349249.121 | |
dc.description.abstract | The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | |
dc.relation.ispartof | Genes and Development | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | BAF | |
dc.subject | BAF180 | |
dc.subject | DNA damage | |
dc.subject | DREAM complex | |
dc.subject | G2/M checkpoint | |
dc.subject | PBRM1 | |
dc.subject | SWI/SNF | |
dc.subject | TP53 | |
dc.subject | cGAS | |
dc.subject | immunotherapy | |
dc.subject | inflammatory signaling | |
dc.subject | p21 | |
dc.title | PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-07-13 | |
dc.date.updated | 2022-08-24T07:27:06Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1101/gad.349249.121 | |
rioxxterms.licenseref.startdate | 2022-07-28 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/35902118 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Epigenetics and Genome Stability | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Breast Radiobiology | |
pubs.publication-status | Published online | |
icr.researchteam | Trans Breast Radiobiol | |
icr.researchteam | Genome Stability | |
dc.contributor.icrauthor | Roumeliotis, Theodoros | |
dc.contributor.icrauthor | Somaiah, Navita | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | Downs, Jessica | |
icr.provenance | Deposited by Prof Jessica Downs on 2022-08-24. Deposit type is initial. No. of files: 1. Files: Genes Dev.-2022-Feng-gad.349249.121.pdf | |