RNA sequence and length contribute to RNA-induced conformational change of TLS/FUS
RNA sequence and length contribute to RNA-induced conformational change of TLS/FUS
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DOI：
10.1038/s41598-020-59496-0
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发表时间：
2020-02-14
影响因子：
4.6
通讯作者：
Katahira, Masato
中科院分区：
文献类型：
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作者：
Hamad, Nesreen;Mashima, Tsukasa;Katahira, Masato
在脂肪肉瘤中易位（TLS）/在肉瘤中融合（FUS）是涉及癌症和神经退行性疾病的多任务DNA/RNA结合蛋白。在DNA损伤后，TLS通过与启动子相关的非编码RNA（pncRNA）结合而被募集到细胞周期蛋白D1基因（CCND 1）的上游区域，所述启动子相关的非编码RNA从上游区域转录并束缚在上游区域。假设与pncRNA的结合导致TLS的构象变化，从而使其能够抑制与组蛋白乙酰转移酶的相互作用并最终抑制CCND 1表达，尽管尚未获得实验证据。在此，TLS结合pncRNA时的闭合到开放构象变化由荧光共振能量转移暗示。全长pncRNA（602个核苷酸）的一个小片段（31个核苷酸）被证明是足够的TLS的构象变化。pncRNA的解剖鉴定了对构象变化至关重要的富含G的RNA序列。RNA的长度也被揭示为构象变化的关键。此外，还证明了TLS的构象变化是由另一个靶DNA和RNA，端粒DNA和含有端粒重复序列的RNA引起的。TLS与靶RNA/DNA结合时的构象变化是其生物学功能所必需的。
Translocated in liposarcoma (TLS)/fused in sarcoma (FUS) is a multitasking DNA/RNA binding protein implicated in cancer and neurodegenerative diseases. Upon DNA damage, TLS is recruited to the upstream region of the cyclin D1 gene (CCND1) through binding to the promotor associated non-coding RNA (pncRNA) that is transcribed from and tethered at the upstream region. Binding to pncRNA is hypothesized to cause the conformational change of TLS that enables its inhibitive interaction with histone acetyltransferases and resultant repression of CCND1 expression, although no experimental proof has been obtained. Here, the closed-to-open conformational change of TLS on binding pncRNA was implied by fluorescence resonance energy transfer. A small fragment (31 nucleotides) of the full-length pncRNA (602 nucleotides) was shown to be sufficient for the conformational change of TLS. Dissection of pncRNA identified the G-rich RNA sequence that is critical for the conformational change. The length of RNA was also revealed to be critical for the conformational change. Furthermore, it was demonstrated that the conformational change of TLS is caused by another target DNA and RNA, telomeric DNA and telomeric repeat-containing RNA. The conformational change of TLS on binding target RNA/DNA is suggested to be essential for biological functions.