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dc.contributor.authorLockwood, N
dc.contributor.authorMartini, S
dc.contributor.authorLopez-Pardo, A
dc.contributor.authorDeiss, K
dc.contributor.authorSegeren, HA
dc.contributor.authorSemple, RK
dc.contributor.authorCollins, I
dc.contributor.authorRepana, D
dc.contributor.authorCobbaut, M
dc.contributor.authorSoliman, T
dc.contributor.authorCiccarelli, F
dc.contributor.authorParker, PJ
dc.date.accessioned2022-05-18T10:04:15Z
dc.date.available2022-05-18T10:04:15Z
dc.identifier.citationCancer research, 2022, 82 (9), pp. 1762 - 1773en
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5137
dc.identifier.eissn1538-7445en_US
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-21-1785en_US
dc.identifier.doi10.1158/0008-5472.can-21-1785
dc.description.abstractTopoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.<h4>Significance</h4>The identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality.en_US
dc.formatPrinten_US
dc.format.extent1762 - 1773en_US
dc.languageengen_US
dc.language.isoengen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCell Line, Tumoren_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectNeoplasmsen_US
dc.subjectDNA Damageen_US
dc.subjectDNA Topoisomerases, Type IIen_US
dc.subjectSignal Transductionen_US
dc.subjectS Phaseen_US
dc.subjectTumor Suppressor Protein p53en_US
dc.subjectPoly-ADP-Ribose Binding Proteinsen_US
dc.titleGenome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells.en
dc.typeJournal Article
dcterms.dateAccepted2022-02-25
rioxxterms.versionAMen
rioxxterms.versionofrecord10.1158/0008-5472.can-21-1785en
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en
dc.relation.isPartOfCancer researchen_US
pubs.issue9en_US
pubs.notesNot knownen_US
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.publication-statusPublisheden_US
pubs.volume82en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMedicinal Chemistry 2
dc.contributor.icrauthorCollins, Ianen_US


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