Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX.
Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX.
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通过诱导端粒 DNA 损伤以及 ATRX 和 DAXX 功能障碍，将端粒酶切换为 ALT 机制
DOI：
10.1038/srep32280
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发表时间：
2016-08-31
影响因子：
4.6
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Hu Y;Shi G;Zhang L;Li F;Jiang Y;Jiang S;Ma W;Zhao Y;Songyang Z;Huang J
端粒酶的激活或端粒的选择性延长（ALT）是肿瘤从功能失调的端粒介导的衰老中逃脱所必需的。抗端粒酶药物可能有效抑制约85-90%端粒酶阳性癌细胞的肿瘤生长。然而，这些细胞在转换为ALT机制后仍有机会绕过药物治疗以维持其端粒完整性。但这种转变背后的机制尚不清楚。本研究以端粒酶阳性癌细胞（HTC75）为研究对象，通过诱导端粒特异性DNA损伤、α -地中海贫血x连锁综合征蛋白（ATRX）敲低和死亡相关蛋白（DAXX）缺失，探索端粒酶- alt开关的机制。令人惊讶的是，在治疗后，在ALT样HTC75细胞中观察到两个重要的ALT标志：ALT相关的早幼粒细胞白血病小体（APBs）和染色体外端粒重复序列的环状DNA。此外，利用CRISPR/Cas9技术敲除hTERT导致alt样HTC75细胞以端粒酶不依赖的方式延长端粒。综上所述，这是首次报道在端粒酶阳性的癌细胞中，诱导端粒DNA损伤、破坏ATRX/DAXX复合体和抑制端粒酶活性可导致ALT开关。
Activation of telomerase or alternative lengthening of telomeres (ALT) is necessary for tumours to escape from dysfunctional telomere-mediated senescence. Anti-telomerase drugs might be effective in suppressing tumour growth in approximately 85–90% of telomerase-positive cancer cells. However, there are still chances for these cells to bypass drug treatment after switching to the ALT mechanism to maintain their telomere integrity. But the mechanism underlying this switch is unknown. In this study, we used telomerase-positive cancer cells (HTC75) to discover the mechanism of the telomerase-ALT switch by inducing telomere-specific DNA damage, alpha-thalassemia X-linked syndrome protein (ATRX) knockdown and deletion of death associated protein (DAXX). Surprisingly, two important ALT hallmarks in the ALT-like HTC75 cells were observed after treatments: ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal circular DNA of telomeric repeats. Moreover, knocking out hTERT by utilizing the CRISPR/Cas9 technique led to telomere elongation in a telomerase-independent manner in ALT-like HTC75 cells. In summary, this is the first report to show that inducing telomeric DNA damage, disrupting the ATRX/DAXX complex and inhibiting telomerase activity in telomerase-positive cancer cells lead to the ALT switch.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
64.5
作者：
Hu J;Hwang SS;Liesa M;Gan B;Sahin E;Jaskelioff M;Ding Z;Ying H;Boutin AT;Zhang H;Johnson S;Ivanova E;Kost-Alimova M;Protopopov A;Wang YA;Shirihai OS;Chin L;DePinho RA
通讯作者：
DePinho RA
影响因子：
21.3
作者：
Liu, D;Safari, A;Zhou, SY
通讯作者：
Zhou, SY
DOI：
10.4161/nucl.20326
发表时间：
2012-05
期刊：
Nucleus (Austin, Tex.)
影响因子：
--
作者：
Chung I;Osterwald S;Deeg KI;Rippe K
通讯作者：
Rippe K
DOI：
10.1126/science.1257216
发表时间：
2015-01-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Flynn RL;Cox KE;Jeitany M;Wakimoto H;Bryll AR;Ganem NJ;Bersani F;Pineda JR;Suvà ML;Benes CH;Haber DA;Boussin FD;Zou L
通讯作者：
Zou L