BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites
BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites
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BGL3 lncRNA 介导 BRCA1/BARD1 复合物在 DNA 损伤位点的保留
DOI：
10.15252/embj.2019104133
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发表时间：
2020-04-29
期刊：
影响因子：
11.4
通讯作者：
Pei, Huadong
中科院分区：
文献类型：
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作者：
Hu, Zhaohua;Mi, Shaojie;Pei, Huadong
长链非编码RNA（lncRNA）是基因组稳定性和人类疾病的新兴调节因子。然而，核lncRNA直接促进DNA损伤反应的分子机制在很大程度上仍然未知。使用RNA反义纯化结合定量质谱（RAP-qMS），我们发现lncRNA BGL 3与PARP 1和BARD 1结合，在同源重组中表现出意想不到的作用。从机制上讲，BGL 3在早期时间点被PARP 1募集到DNA双链断裂（DSB），这需要它与PARP 1的DNA结合结构域相互作用。BGL 3还结合C-末端BRCT结构域和BARD 1的内部区域（氨基酸127-424），其介导BRCA 1/BARD 1复合物与其结合配偶体（如HP 1 γ和RAD 51）的相互作用，导致BRCA 1/BARD 1保留在DSB。BGL 3耗尽的细胞显示基因组不稳定性，并且对DNA损伤试剂敏感。总的来说，我们的研究结果强调了RNA作为DNA损伤反应途径中的介体分子的生物化学多功能性，这会影响BRCA 1/BARD 1在DSB中的积累。
Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1 gamma and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.