Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers.
Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers.
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DOI：
10.1073/pnas.1720391115
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发表时间：
2018-05-01
影响因子：
11.1
通讯作者：
Wong LH
中科院分区：
文献类型：
--
作者：
Udugama M;Sanij E;Voon HPJ;Son J;Hii L;Henson JD;Chan FL;Chang FTM;Liu Y;Pearson RB;Kalitsis P;Mann JR;Collas P;Hannan RD;Wong LH
我们证明，ATRX维持核糖体DNA（rDNA）异染色质的形成和稳定性。ATRX耗尽的细胞遭受广泛的rDNA拷贝丢失，导致核糖体RNA转录输出减少和对RNA聚合酶I（Pol I）抑制的敏感性增加。支持这些数据，我们还检测到ATRX突变ALT阳性人原发性肿瘤样品中rDNA拷贝减少，以及人ALT癌细胞系对RNA Pol I转录抑制剂的敏感性增加。我们的研究强调了Pol I转录抑制剂治疗ATRX突变癌症的治疗潜力。ATRX（α地中海贫血/X连锁精神发育迟滞）与DAXX复合，将组蛋白变体H3.3存款到重复异染色质中。最近的癌症基因组测序研究揭示了ATRX的突变及其与ALT（端粒替代延长）激活的关联。在这里，我们报告消耗ATRX在小鼠ES细胞导致核糖体RNA基因（rDNA）拷贝数的选择性损失。支持这一点，ATRX突变的人ALT阳性肿瘤也显示出比ALT阴性肿瘤显著更低的rDNA拷贝。进一步的研究表明，rDNA拷贝丢失和重复不稳定性是由H3.3沉积的破坏引起的，因此在不存在ATRX的情况下，rDNA重复处的异染色质形成失败。我们还发现，ATRX耗尽的细胞减少核糖体RNA转录输出，并显示出增加的敏感性RNA聚合酶I（Pol I）转录抑制剂CX 5461。此外，人ALT阳性癌细胞系对CX 5461治疗也更敏感。我们的研究通过rDNA稳定性的丧失提供了ATRX功能丧失对肿瘤发生的贡献的见解，并表明了在ALT癌症中靶向Pol I转录的治疗潜力。
We demonstrate that ATRX maintains ribosomal DNA (rDNA) heterochromatin formation and stability. ATRX-depleted cells suffer extensive rDNA copy loss, resulting in a reduced ribosomal RNA transcription output and an increased sensitivity to RNA polymerase I (Pol I) inhibition. Supporting these data, we have also detected reduced rDNA copy in ATRX mutated ALT-positive human primary tumor samples and increased sensitivity of human ALT cancer cell lines to RNA Pol I transcription inhibitor. Our study highlights the therapeutic potential of Pol I transcription inhibitors for the treatment of ATRX-mutated cancers. 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.
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影响因子：
12.3
作者：
Day DS;Luquette LJ;Park PJ;Kharchenko PV
通讯作者：
Kharchenko PV
影响因子：
14.9
作者：
Udugama M;M Chang FT;Chan FL;Tang MC;Pickett HA;R McGhie JD;Mayne L;Collas P;Mann JR;Wong LH
通讯作者：
Wong LH
影响因子：
8.8
作者：
Voon HP;Hughes JR;Rode C;De La Rosa-Velázquez IA;Jenuwein T;Feil R;Higgs DR;Gibbons RJ
通讯作者：
Gibbons RJ
影响因子：
4.9
作者：
Bao W;Kojima KK;Kohany O
通讯作者：
Kohany O
影响因子：
30.8
作者：
Gibbons, RJ;McDowell, TL;Higgs, DR
通讯作者：
Higgs, DR