PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase.
PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase.
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DOI：
10.1101/gad.313460.118
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发表时间：
2018-05-01
影响因子：
10.5
通讯作者：
Lingner J
中科院分区：
文献类型：
--
作者：
Ahmed W;Lingner J
在这项研究中，Ahmed等人证明端粒的氧化损伤抑制癌细胞染色体末端的端粒酶活性。删除两种抗氧化酶PRDX 1和MTH 1，需要保护端粒免受氧化损伤，导致端粒DNA的损失，在氧浓度依赖性的方式，由于抑制端粒酶，从而提供了新的见解的作用，需要保护端粒免受氧化的抗氧化系统。端粒酶通过在染色体末端添加重复DNA序列来抵消生殖细胞、干细胞和癌细胞中的端粒缩短和细胞衰老。端粒容易受到活性氧（ROS）的损伤，但端粒氧化对端粒长度的影响以及保护端粒免受ROS介导的端粒损伤的机制尚不清楚。特别是，在端粒底物3′端的8-氧代鸟嘌呤核苷酸在体外抑制端粒酶，而在内部位置，它们抑制G-四链体的形成，因此被认为是促进端粒酶活性。在这里，我们破坏癌细胞中的过氧化物氧还蛋白1（PRDX 1）和7，8-二氢-8-氧代鸟嘌呤三磷酸酶（MTH 1）基因，并证明PRDX 1和MTH 1合作，以防止基因组中氧化鸟嘌呤的积累。PRDX 1和MTH 1的同时破坏导致端粒的ROS浓度依赖性持续缩短，这是由于端粒酶有效抑制端粒延伸。我们的研究结果确定了保护端粒免受氧化所需的抗氧化系统，并且是通过端粒酶赋予癌细胞永生来维持端粒所必需的。
In this study, Ahmed et al. demonstrate that oxidative damage of telomeres inhibits telomerase activity at chromosome ends in cancer cells. Deletion of two antioxidant enzymes—PRDX1 and MTH1, needed for protecting telomeres from oxidative damage—results in loss of telomeric DNA in an oxygen concentration-dependent manner due to inhibition of telomerase, thus providing new insights into the role of antioxidant systems that are required to protect telomeres from oxidation. Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length and the mechanisms that protect from ROS-mediated telomere damage are not well understood. In particular, 8-oxoguanine nucleotides at 3′ ends of telomeric substrates inhibit telomerase in vitro, whereas, at internal positions, they suppress G-quadruplex formation and were therefore proposed to promote telomerase activity. Here, we disrupt the peroxiredoxin 1 (PRDX1) and 7,8-dihydro-8-oxoguanine triphosphatase (MTH1) genes in cancer cells and demonstrate that PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 leads to ROS concentration-dependent continuous shortening of telomeres, which is due to efficient inhibition of telomere extension by telomerase. Our results identify antioxidant systems that are required to protect telomeres from oxidation and are necessary to allow telomere maintenance by telomerase conferring immortality to cancer cells.
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DOI：
10.1038/nrm.2016.43
发表时间：
2016-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Lazzerini-Denchi E;Sfeir A
通讯作者：
Sfeir A
DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Lange T
通讯作者：
de Lange T
影响因子：
4.5
作者：
Britt-Compton, Bethan;Wyllie, Fiona;Baird, Duncan M.
通讯作者：
Baird, Duncan M.
影响因子：
4
作者：
Ahmed, Shaheda;Passos, Joao F.;Saretzki, Gabriele
通讯作者：
Saretzki, Gabriele
影响因子：
56.9
作者：
Lingner, J;Hughes, TR;Cech, TR
通讯作者：
Cech, TR