Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition.
Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition.
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DOI：
10.1093/nar/gkx1312
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发表时间：
2018-02-28
影响因子：
14.9
通讯作者：
Ahn K
中科院分区：
文献类型：
--
作者：
Choi J;Hwang SY;Ahn K
长散布核元件1是一种自主的非长末端重复反转录转座子，占人类基因组的约17%。其自发的反转录转座和可遗传的L1插入的积累可能导致基因组不稳定和散发性疾病。莫洛尼白血病病毒10同源物（MOV 10），一个假定的RNA解旋酶，已被牵连在抑制L1复制，虽然其潜在的作用机制仍然不清楚。此外，MOV 10介导的L1调节在人类疾病中的生理相关性尚未被研究。使用蛋白质组学方法，我们鉴定了RNASEH 2作为MOV 10的结合伴侣。我们发现，MOV 10与RNASEH 2相互作用，它们的相互作用是限制L1反转录转座的关键。RNASEH 2和MOV 10共定位于细胞核中，并且RNASEH 2以MOV 10依赖性方式结合L1 RNA。小发夹RNA介导的RNASEH 2A或MOV 10的缺失导致L1特异性RNA-DNA杂合体的积累，表明它们有助于防止逆转录转座过程中重要的L1异源双链体的形成。此外，我们发现RNASEH 2-MOV 10介导的L1限制下调滑膜细胞中类风湿关节炎相关炎性细胞因子和基质降解蛋白酶的表达，暗示它们与疾病易感性方面的疾病发展之间存在潜在的因果关系。
Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined. Using a proteomic approach, we identified RNASEH2 as a binding partner of MOV10. We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 heteroduplexes during retrotransposition. Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.
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