Dynamic action of an intrinsically disordered protein in DNA compaction that induces mycobacterial dormancy

• Published in: Nucleic acids research 2024-01, Vol.52 (2), p.816-830
• Main Authors: Nishiyama, Akihito, Shimizu, Masahiro, Narita, Tomoyuki, Kodera, Noriyuki, Ozeki, Yuriko, Yokoyama, Akira, Mayanagi, Kouta, Yamaguchi, Takehiro, Hakamata, Mariko, Shaban, Amina Kaboso, Tateishi, Yoshitaka, Ito, Kosuke, Matsumoto, Sohkichi
• Format: Article
• Language: English
• Subjects: DNA; Histones; Humans; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Molecular Biology; Mycobacterium - genetics; Mycobacterium - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkad1149

Abstract 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. Graphical Abstract Graphical Abstract