Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers

M Udugama; E Sanij; HPJ Voon; J Son; L Hii; JD Henson; F Lyn Chan; FTM Chang; Y Liu; RB Pearson; P Kalitsis; JR Mann; P Collas; RD Hannan; LH Wong

Journal article

Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers

M Udugama, E Sanij, HPJ Voon, J Son, L Hii, JD Henson, F Lyn Chan, FTM Chang, Y Liu, RB Pearson, P Kalitsis, JR Mann, P Collas, RD Hannan, LH Wong

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2018

DOI: 10.1073/pnas.1720391115

Download PDF

Abstract

ATRX (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 form..

View full abstract

University of Melbourne Researchers

Elaine Sanij Author

Richard Pearson Author

Paul Kalitsis Author

Related Projects (1)

ONCOGENIC SIGNALING AND CANCER THERAPY

Central to improving the management of patients with cancer is an understanding of the molecular drivers of cancer. Based on our fundamental..

Grants

Awarded by Kreftforeningen

Funding Acknowledgements

We thank HSA Biobank (University of New South Wales) for providing the tumor tissue samples. This work was supported by the Norwegian Cancer Society and the Research Council of Norway (to P.C.); an Australia Research Council Future Fellowship award (to L.H.W.); National Health and Medical Research Council Program Grant 1053792 (to R.B.P. and R.D.H.), senior research fellowships (to R.B.P. and R.D.H.), and a project grant (to L.H.W.); and a Cure Brain Cancer Foundation Australia project grant (to L.H.W. and H.P.J.V.).