School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202209463. doi: 10.1002/anie.202209463. Epub 2022 Aug 23.
Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as a genome "caretaker" that processes structured DNA. In contrast, our knowledge of how BLM behaves on single-stranded (ss) DNA is still limited. Here, we demonstrate that BLM possesses the intrinsic ability for phase separation and can co-phase separate with ssDNA to form dynamically arrested protein/ssDNA co-condensates. The introduction of ATP potentiates the capability of BLM to condense on ssDNA, which further promotes the compression of ssDNA against a resistive force of up to 60 piconewtons. Moreover, BLM is also capable of condensing replication protein A (RPA)- or RAD51-coated ssDNA, before which it generates naked ssDNA by dismantling these ssDNA-binding proteins. Overall, our findings identify an unexpected characteristic of a DNA helicase and provide a new angle of protein/ssDNA co-condensation for understanding the genomic instability caused by BLM overexpression under diseased conditions.
布卢姆综合征蛋白 (BLM) 是一种保守的 RecQ 家族解旋酶，参与维持基因组稳定性。BLM 被广泛认为是一种处理结构 DNA 的基因组“守护者”。相比之下，我们对 BLM 在单链 (ss) DNA 上的行为的了解仍然有限。在这里，我们证明 BLM 具有内在的相分离能力，并可以与 ssDNA 共同相分离，形成动态停滞的蛋白/ssDNA 共凝聚物。引入 ATP 增强了 BLM 在 ssDNA 上浓缩的能力，这进一步促进了 ssDNA 对高达 60 皮牛顿的阻力的压缩。此外，BLM 还能够浓缩复制蛋白 A (RPA) 或 RAD51 包裹的 ssDNA，在此之前，它通过拆除这些 ssDNA 结合蛋白来产生裸露的 ssDNA。总的来说，我们的发现确定了一种 DNA 解旋酶的意外特征，并为理解疾病条件下 BLM 过表达引起的基因组不稳定性提供了一个蛋白/ssDNA 共凝聚的新视角。
