Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants
Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants
复制标题
癌症相关的 SAMHD1 突变体对 LINE-1 逆转录转座的调节有缺陷。
DOI：
10.1016/j.bbrc.2019.08.155
复制
发表时间：
2019-11-05
影响因子：
3.1
通讯作者：
Yu, XiaoFang
中科院分区：
文献类型：
--
作者：
Gao, Wenying;Li, Guangquan;Yu, XiaoFang
长期散布的核元素（LINE-1）现在被认为是人类中唯一主动的自主移动DNA，在癌症的启动和进展过程中，LINE-1逆转录活性与逆转录置换活动相关联并波动。但是，癌症中线1活性增加的机制知之甚少。据报道，SAMHD1是线路1逆转录的有效抑制剂，SAMHD1突变经常与癌症发展有关。为了了解与癌症相关的SAMHD1突变体是否影响线路1活性，我们探索了一些已知与癌症发展相关的人类突变体的生化和细胞特性。大多数已测试的SAMHD1癌症相关突变在行抑制中都是有缺陷的。有趣的是，我们还发现SAMHD1突变体K288T的DNTPase活性有缺陷，但对线路1逆转录的有效活性。这些发现表明，线1抑制不仅取决于SAMHD1的DNTPase活性。相反，SAMHD1抑制ORF2P介导的LINE-1 RNP逆转录的能力与SAMHD1介导的LINE-1抑制作用相关。总之，我们的数据还可以促进对SAMHD1抑制内源性线1元素的更深入了解。 （c）2019 Elsevier Inc.保留所有权利。
Long interspersed nuclear elements (LINE-1) is now considered as the only active autonomous mobile DNA in humans, LINE-1 retrotransposition activities are associated with and fluctuate during cancer initiation and progression; however, the mechanism underlying the increased LINE-1 activity in cancer is poorly understood. SAMHD1 has been reported to be a potent inhibitor of LINE-1 retrotransposition, and SAMHD1 mutations are frequently associated with cancer development. To gain insights on whether cancer-related SAMHD1 mutants affect LINE-1 activity, we explored the biochemical and cellular properties of some human mutants known correlate with the development of cancer. Most of the tested SAMHD1 cancer-related mutations were defective in LINE-1 inhibition. Interestingly we also found that SAMHD1 mutant K288T was defective for dNTPase activity but showed potent activity against LINE-1 retrotransposition. These findings suggest that LINE-1 inhibition does not depend solely on the dNTPase activity of SAMHD1. In contrast, SAMHD1's ability to inhibit ORF2p-mediated LINE-1 RNP reverse transcription was correlated with SAMHD1-mediated LINE-1 inhibition. Together, our data could also facilitate the deeper understanding for the inhibition of endogenous LINE-1 elements by SAMHD1. (C) 2019 Elsevier Inc. All rights reserved.