Transient Activation of the ALT Pathway in Human Primary Fibroblasts Exposed to High-LET Radiation
Transient Activation of the ALT Pathway in Human Primary Fibroblasts Exposed to High-LET Radiation
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DOI：
10.1667/rr2127.1
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发表时间：
2010-11-01
影响因子：
3.4
通讯作者：
Sgura, A.
中科院分区：
文献类型：
--
作者：
Berardinelli, F.;Antoccia, A.;Sgura, A.
已确定高LET辐射可有效诱导染色体畸变。然而，关于质子对端粒维持的影响的数据，涉及基因组稳定性，是稀缺和矛盾的。在这里，我们证明了高LET质子诱导端粒延长在人类原代成纤维细胞，这种延长不涉及端粒酶，支持的假设，即高LET辐射能够激活端粒酶独立的机制。在缺乏端粒酶的肿瘤细胞中，存在一种或多种用于端粒维持的非端粒酶机制，其被称为端粒替代性延长（ALT）。由于ALT细胞的特征是端粒的重组事件，称为端粒-姐妹染色单体交换（T-SCE），以及端粒和早幼粒细胞白血病蛋白（PAIL）的共定位，我们分析了T-SCE和PML。我们的结果表明，高LET质子诱导T-SCE增加2.5倍，并导致PML蛋白和端粒DNA的共定位。此外，我们的数据表明，ALT途径可以在诱导严重的DNA损伤后在人原代细胞中被激活。因此，由于已知端粒参与染色体维持，因此本工作可能有助于阐明电离辐射诱导基因组不稳定性的机制。(C)2010年，辐射研究学会
It is well established that high-LET radiations efficiently induce chromosome aberrations. However, data on the effect of protons on telomere maintenance, as involved in genomic stability, are scarce and contradictory. Here we demonstrate that high-LET protons induce telomere lengthening in human primary fibroblasts and that this elongation does not involve the telomerase enzyme, supporting the hypothesis that high-LET radiations are able to activate a telomerase-independent mechanism. In tumor cells that lack telomerase, one or more non-telomerase mechanisms for telomere maintenance are present, which are termed alternative lengthening of telomeres (ALT). Since ALT cells are characterized by recombinational events at telomeres, known as telomeric-sister chromatid exchanges (T-SCE), and colocalization of telomeres and premyelocytic leukemia protein (PAIL), we analyzed both T-SCE and PML. Our results show that high-LET protons induce a 2.5-fold increase of T-SCE and a colocalization of PML protein and telomeric DNA. Furthermore, our data show that the ALT pathway can be activated in human primary cells after induction of severe DNA damage. Thus, since telomeres are known to be involved in chromosome maintenance, the present work may contribute in the elucidation of the mechanism by which ionizing radiation induces genomic instability. (C) 2010 by Radiation Research Society