Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers
2018
ATRX(
alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit
histone variantH3.3 into repetitive
heterochromatin. Recent genome sequencing studies in cancers have revealed mutations in
ATRXand their association with ALT (alternative lengthening of telomeres) activation. Here we report depletion of
ATRXin mouse ES cells leads to selective loss in
ribosomal RNAgene (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
heterochromatinformation at rDNA repeats in the absence of
ATRX. We also find that
ATRX-depleted cells are reduced in
ribosomal RNAtranscription 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
ATRXloss of function to tumorigenesis through the loss of rDNA stability and suggests the therapeutic potential of targeting Pol I transcription in ALT cancers.
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