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dc.contributor.authorUdugama, M
dc.contributor.authorSanij, E
dc.contributor.authorVoon, HPJ
dc.contributor.authorSon, J
dc.contributor.authorHii, L
dc.contributor.authorHenson, JD
dc.contributor.authorChan, FL
dc.contributor.authorChang, FTM
dc.contributor.authorLiu, Y
dc.contributor.authorPearson, RB
dc.contributor.authorKalitsis, P
dc.contributor.authorMann, JR
dc.contributor.authorCollas, P
dc.contributor.authorHannan, RD
dc.contributor.authorWong, LH
dc.date.accessioned2020-12-17T03:21:10Z
dc.date.available2020-12-17T03:21:10Z
dc.date.issued2018-05-01
dc.identifierpii: 1720391115
dc.identifier.citationUdugama, M., Sanij, E., Voon, H. P. J., Son, J., Hii, L., Henson, J. D., Chan, F. L., Chang, F. T. M., Liu, Y., Pearson, R. B., Kalitsis, P., Mann, J. R., Collas, P., Hannan, R. D. & Wong, L. H. (2018). Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115 (18), pp.4737-4742. https://doi.org/10.1073/pnas.1720391115.
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/11343/254849
dc.description.abstractATRX (alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitive heterochromatin. Recent genome sequencing studies in cancers have revealed mutations in ATRX and their association with ALT (alternative lengthening of telomeres) activation. Here we report depletion of ATRX in mouse ES cells leads to selective loss in ribosomal RNA gene (rDNA) copy number. Supporting this, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA copy than ALT-negative tumors. Further investigation shows that the rDNA copy loss and repeat instability are caused by a disruption in H3.3 deposition and thus a failure in heterochromatin formation at rDNA repeats in the absence of ATRX. We also find that ATRX-depleted cells are reduced in ribosomal RNA transcription output and show increased sensitivity to RNA polymerase I (Pol I) transcription inhibitor CX5461. In addition, human ALT-positive cancer cell lines are also more sensitive to CX5461 treatment. Our study provides insights into the contribution of ATRX loss of function to tumorigenesis through the loss of rDNA stability and suggests the therapeutic potential of targeting Pol I transcription in ALT cancers.
dc.languageEnglish
dc.publisherNATL ACAD SCIENCES
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.titleRibosomal DNA copy loss and repeat instability in ATRX-mutated cancers
dc.typeJournal Article
dc.identifier.doi10.1073/pnas.1720391115
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentPaediatrics (RCH)
melbourne.source.titleProceedings of the National Academy of Sciences of USA
melbourne.source.volume115
melbourne.source.issue18
melbourne.source.pages4737-4742
melbourne.identifier.nhmrc1053792
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1323730
melbourne.contributor.authorSanij, Elaine
melbourne.contributor.authorKalitsis, Paul
melbourne.contributor.authorPearson, Richard
melbourne.contributor.authorSon, Jinbae
melbourne.contributor.authorHannan, Ross
dc.identifier.eissn1091-6490
melbourne.identifier.fundernameidNHMRC, 1053792
melbourne.accessrightsOpen Access


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