GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability
GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability
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GUARDIN 是一种 p53 响应性长非编码 RNA，对于基因组稳定性至关重要
DOI：
10.1038/s41556-018-0066-7
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发表时间：
2018-04-01
影响因子：
21.3
通讯作者：
Wu, Mian
中科院分区：
文献类型：
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作者：
Hu, Wang Lai;Jin, Lei;Wu, Mian
参与DNA损伤反应p53通路的长链非编码rna （long non-coding RNAs, lncRNAs）正在迅速扩大，但lncRNAs是否在维持DNA的新生结构中发挥作用尚不清楚。在这里，我们证明了p53应答的lncRNA GUARDIN对于在稳态条件下和暴露于外源性基因毒性胁迫后维持基因组完整性是重要的。GUARDIN通过隔离microRNA-23a来维持端粒重复结合因子2 （TRF2）的表达，从而防止染色体端到端融合。此外，GUARDIN还通过作为RNA支架促进BRCA1和BRCA1相关环结构域蛋白1 （BARD1）的异源二聚化来维持乳腺癌1 （BRCA1）的稳定性。因此，GUARDIN沉默可触发细胞凋亡和衰老，增强额外基因毒性应激的细胞毒性，并抑制癌症异种移植物生长。因此，GUARDIN可能成为癌症治疗的靶点。
The list of long non-coding RNAs (lncRNAs) involved in the p53 pathway of the DNA damage response is rapidly expanding, but whether lncRNAs have a role in maintaining the de novo structure of DNA is unknown. Here, we demonstrate that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress. GUARDIN is necessary for preventing chromosome end-to-end fusion through maintaining the expression of telomeric repeat-binding factor 2 (TRF2) by sequestering microRNA-23a. Moreover, GUARDIN also sustains breast cancer 1 (BRCA1) stability by acting as an RNA scaffold to facilitate the heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). As such, GUARDIN silencing triggered apoptosis and senescence, enhanced cytotoxicity of additional genotoxic stress and inhibited cancer xenograft growth. Thus, GUARDIN may constitute a target for cancer treatment.