Department of Bacteriology, Niigata University School of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
Nano Life Science Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa 920-1192, Japan.
Nucleic Acids Res. 2024 Jan 25;52(2):816-830. doi: 10.1093/nar/gkad1149.
Mycobacteria are the major human pathogens with the capacity to become dormant persisters. Mycobacterial DNA-binding protein 1 (MDP1), an abundant histone-like protein in dormant mycobacteria, induces dormancy phenotypes, e.g. chromosome compaction and growth suppression. For these functions, the polycationic intrinsically disordered region (IDR) is essential. However, the disordered property of IDR stands in the way of clarifying the molecular mechanism. Here we clarified the molecular and structural mechanism of DNA compaction by MDP1. Using high-speed atomic force microscopy, we observed that monomeric MDP1 bundles two adjacent DNA duplexes side-by-side via IDR. Combined with coarse-grained molecular dynamics simulation, we revealed the novel dynamic DNA cross-linking model of MDP1 in which a stretched IDR cross-links two DNA duplexes like double-sided tape. IDR is able to hijack HU function, resulting in the induction of strong mycobacterial growth arrest. This IDR-mediated reversible DNA cross-linking is a reasonable model for MDP1 suppression of the genomic function in the resuscitable non-replicating dormant mycobacteria.
分枝杆菌是主要的人类病原体，具有成为休眠持久菌的能力。分枝杆菌 DNA 结合蛋白 1（MDP1）是休眠分枝杆菌中丰富的组蛋白样蛋白，可诱导休眠表型，如染色体紧缩和生长抑制。对于这些功能，多阳离子固有无序区（IDR）是必不可少的。然而，IDR 的无序性质阻碍了对分子机制的澄清。在这里，我们阐明了 MDP1 压缩 DNA 的分子和结构机制。使用高速原子力显微镜，我们观察到单体 MDP1 通过 IDR 并排捆绑两个相邻的 DNA 双链。结合粗粒度分子动力学模拟，我们揭示了 MDP1 的新型动态 DNA 交联模型，其中伸展的 IDR 像双面胶带一样交联两个 DNA 双链。IDR 能够劫持 HU 功能，导致强烈的分枝杆菌生长停滞。这种 IDR 介导的可逆 DNA 交联是 MDP1 抑制可复苏非复制休眠分枝杆菌基因组功能的合理模型。
