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


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.

SUBMITTER: Udugama M 

PROVIDER: S-EPMC5939086 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Udugama Maheshi M   Sanij Elaine E   Voon Hsiao P J HPJ   Son Jinbae J   Hii Linda L   Henson Jeremy D JD   Chan F Lyn FL   Chang Fiona T M FTM   Liu Yumei Y   Pearson Richard B RB   Kalitsis Paul P   Mann Jeffrey R JR   Collas Philippe P   Hannan Ross D RD   Wong Lee H LH  

Proceedings of the National Academy of Sciences of the United States of America 20180418 18


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  ...[more]

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