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Proc Natl Acad Sci U S A. 2018 May 1;115(18):4737-4742. doi: 10.1073/pnas.1720391115. Epub 2018 Apr 18.

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

Author information

1
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
2
Research Division, Peter MacCallum Cancer Centre, Parkville, VIC 2010, Australia.
3
Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia.
4
Cancer Cell Immortality Group, Adult Cancer Program, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2052, Australia.
5
College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan Province, 471023, China.
6
Sir Peter MacCallum Department of Oncology, The University of Melbourne, VIC 3010, Australia.
7
Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
8
Department of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, VIC 3052, Australia.
9
Genome Modification Platform, Monash University, Clayton, VIC 3800, Australia.
10
Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
11
Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
12
The ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia.
13
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; lee.wong@monash.edu.

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 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.

KEYWORDS:

ALT; ATRX; H3.3; ribosomal DNA; telomeres

PMID:
29669917
PMCID:
PMC5939086
DOI:
10.1073/pnas.1720391115
[Indexed for MEDLINE]
Free PMC Article

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