DNA damage induces alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA
DNA damage induces alternative lengthening of telomeres (ALT)-associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA
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DOI：
10.1158/0008-5472.can-07-1556
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发表时间：
2007-08-01
期刊：
影响因子：
11.2
通讯作者：
Reddel, Roger R.
中科院分区：
文献类型：
--
作者：
Fasching, Clare L.;Neumann, Axel A.;Reddel, Roger R.
脊椎动物的线性染色体终止于端粒，端粒由串联重复的六聚体序列 5'TTAGGG3'组成。端粒形成保护环结构（t 环），这被认为可以防止它们被识别为双链断裂。大约 10% 的人类肿瘤通过使用重组介导的替代性端粒延长 (ALT) 机制来防止端粒缩短。 ALT 阳性人类细胞含有染色体外端粒重复 (ECTR) DNA，可以是环状或线状。有人提出 ECTR 可能是由涉及 t 环的重组事件产生的。 ALT 阳性细胞群中的一部分细胞含有早幼粒细胞白血病 (PML) 核体，其中含有端粒 DNA 和端粒结合蛋白，称为 ALT 相关 PML 体 (APB)。尽管 APB 的存在对于确定肿瘤和细胞系是否使用 ALT 机制非常有用，但 APB 的功能尚不清楚。此前已有研究表明，端粒 DNA 特别容易受到过氧化氢和 N-甲基-N-硝基-N-亚硝基胍的损伤。我们在此报告，这些 DNA 损伤剂在 ALT 细胞中诱导线性和环状 ECTR DNA，并增加含有 APB 的细胞比例。我们部分纯化了 APB，并表明它们所含的端粒重复 DNA 主要是线性的。我们认为 APB 的功能是隔离线性端粒 DNA。
The linear chromosomes of vertebrates terminate in telomeres that consist of a tandemly repeated hexameric sequence, 5 ' TTAGGG3 '. Telomeres form a protective loop structure (t-loop), which is thought to prevent them from being recognized as a double-strand break. Approximately 10% of human tumors prevent shortening of their telomeres by using a recombination-mediated alternative lengthening of telomeres (ALT) mechanism. ALT-positive human cells contain extrachromosomal telomere repeat (ECTR) DNA that may either be circular or linear. It has been proposed that ECTR may be generated by recombination events involving the t-loop. A proportion of the cells within ALT-positive cell populations contain promyelocytic leukemia (PML) nuclear bodies that contain telomeric DNA and telomere-binding proteins that are called ALT-associated PML bodies (APB). Although the presence of APBs is very useful for determining whether tumors and cell lines use the ALT mechanism, the function of APBs is unknown. It has previously been shown that telomeric DNA is particularly susceptible to damage by hydrogen peroxide and N-methyl-N-nitro-N-nitrosoguanidine. We report here that these DNA-damaging agents induce both linear and circular ECTR DNA in ALT cells and increase the proportion of cells that contain APBs. We partially purified APBs and showed that the telomeric repeat DNA they contain is predominantly linear. We propose that a function of APBs is to sequester linear telomeric DNA.