Abstract
The architecture of the genome influences the functions of DNA from bacteria to eukaryotes. Intrinsically disordered regions (IDR) of eukaryotic histones have pivotal roles in various processes of gene expression. IDR is rare in bacteria, but interestingly, mycobacteria produce a unique histone-like protein, MDP1 that contains a long C-terminal IDR. Here we analyzed the role of IDR in MDP1 function. By employing Mycobacterium smegmatis that inducibly expresses MDP1 or its IDR-deficient mutant, we observed that MDP1 induces IDR-dependent DNA compaction. MDP1-IDR is also responsible for the induction of growth arrest and tolerance to isoniazid, a front line tuberculosis drug that kills growing but not growth-retardated mycobacteria. We demonstrated that MDP1-deficiency and conditional knock out of MDP1 cause spreading of the M. smegmatis genome in the stationary phase. This study thus demonstrates for the first time a C-terminal region-dependent organization of the genome architecture by MDP1, implying the significance of IDR in the function of bacterial histone-like protein.
Highlights
Histone is a primary component of the eukaryotic nucleosome, where DNA wraps around an octamer of four core histones
In order to know the function of the C-terminal Intrinsically disordered regions (IDR) of Mycobacterial DNA-binding protein 1 (MDP1), we first constructed plasmids to complement Δmdp[1] by whole MDP1 or its C-terminal IDR deletion mutant (NTD)
We observed a normal growth rate of Δmdp[1] transformed with a plasmid that expresses N-terminal 99-amino acid domain (NTD) (Supplementary Fig. S2A, NTD) by its own promoter or Psmyc promoter. This agreed with the growth suppressive effects of whole MDP1, as we previously indicated[20], implying the importance of IDR on this growth suppressive effect
Summary
Histone is a primary component of the eukaryotic nucleosome, where DNA wraps around an octamer of four core histones (two of each histone H2A, H2B, H3, and H4). Linker histones (H1 and H5) bind to the nucleosome and adjacent linker DNA These histones possess intrinsically disordered regions (IDR), which lack typical secondary and tertiary structures[1]. Polycationic C-terminal IDR of histone H1 binds to DNA or negatively charged protein domains. Bacterial histone-like proteins, such as HU (initially reported as a heat stable DNA-binding protein of Escherichia coli strain U93)[11], integration host factor (IHF)[12], and histone-like nucleoid structuring protein (H-NS)[13] are small basic proteins (10–15 kDa), which share functions with histones, especially in the DNA-compaction capacity[14,15]. All the examined mycobacterial species produce a unique histone-like protein designated Mycobacterial DNA-binding protein 1 (MDP1), which contains a long IDR unlike histone-like proteins in other bacteria. The N-terminal 99-amino acid domain (NTD) of MDP1 is HU-like and highly conserved in mycobacterial species[14,17,18,19]. The down-regulation of replication and cellular metabolism by MDP1 was suggested to contribute to the long-term survival of mycobacteria[22]
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