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 HP1γ 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.

中文翻译：

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BGL3 lncRNA介导BRCA1 / BARD1复合物在DNA损伤位点的保留。

长非编码RNA（lncRNA）是基因组稳定性和人类疾病的新兴调节剂。然而，核lncRNAs直接促进DNA损伤反应的分子机制仍然未知。通过将RNA反义纯化与定量质谱（RAP-qMS）结合使用，我们发现lncRNA BGL3与PARP1和BARD1结合，在同源重组中表现出意想不到的作用。从机理上讲，BGL3在早期的某个时间点被PARP1募集到DNA双链断裂（DSB），这需要它与PARP1的DNA结合域相互作用。BGL3还结合BARD1的C末端BRCT结构域和一个内部区域（氨基酸127–424），该区域介导BRCA1 / BARD1复合物与其结合伴侣如HP1γ和RAD51的相互作用，导致BRCA1 / BARD1保留在DSB上。耗尽BGL3的细胞显示出基因组不稳定，并且对DNA破坏试剂敏感。总体而言，我们的发现强调了RNA作为DNA损伤反应途径中的介导分子的生化多样性，这会影响BRCA1 / BARD1在DSB处的积累。