Structural basis of paralog-specific KDM2A/B nucleosome recognition

Spangler, Cathy J; Skrajna, Aleksandra; Foley, Caroline A.; Nguyen, Anh; Budziszewski, Gabrielle R.; Azzam, Dalal N.; Arteaga, Eyla Cristina; Simmons, Holly C.; Smith, Charlotte B.; Wesley, Nathaniel A.; Wilkerson, Emily M.; McPherson, Jeanne-Marie E.; Kireev, Dmitri; James, Lindsey I.; Frye, Stephen V.; Goldfarb, Dennis; McGinty, Robert K.

doi:10.1038/s41589-023-01256-y

“…9a) Interestingly, mutation of Hs H2A-Asn68 was recently shown to reduce binding to multiple chromatin-associated proteins in a proteome-wide screen. 53 Both the surface charge and shape alterations are also conserved in our predicted models of five other kinetoplastid histone octamers (Supplementary Fig. 9b).…”

Section: Altered Octamer Topology In the T Brucei Ncp Leads To An Aty...mentioning

confidence: 55%

Histone divergence inTrypanosoma bruceiresults in unique alterations to nucleosome structure

Deák

¹

,

Wapenaar

²

,

Sandoval

³

et al. 2023

Preprint

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Eukaryotes have a multitude of diverse mechanisms for organising and using their genomes, but the histones that make up chromatin are highly conserved. Unusually, histones from kinetoplastids are highly divergent. The structural and functional consequences of this variation are unknown. Here, we have biochemically and structurally characterised nucleosome core particles (NCPs) from the kinetoplastid parasite Trypanosoma brucei. A structure of the T. brucei NCP reveals that global histone architecture is conserved, but specific sequence alterations lead to distinct DNA and protein interaction interfaces. The T. brucei NCP is unstable and has weakened overall DNA binding. However, dramatic changes at the H2A-H2B interface introduce local reinforcement of DNA contacts. The T. brucei acidic patch has altered topology and is refractory to known binders, indicating that the nature of chromatin interactions in T. brucei may be unique. Overall, our results provide a detailed molecular basis for understanding evolutionary divergence in chromatin structure.

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“…While three of the canonical residues have undergone mild glutamate-to-aspartate substitutions ( Tb H2A-Asp93, Tb H2A-Asp94 and Tb H2B-Asp93), a lysine substitution ( Tb H2A-Lys68 from Hs H2A-Asn68) is in close proximity to the patch (Figure 6C ). This substitution is conserved across the kinetoplastids ( Supplementary Figure S9A ) Interestingly, mutation of Hs H2A-Asn68 was recently shown to reduce binding to multiple chromatin-associated proteins in a proteome-wide screen ( 89 ). Both the surface charge and shape alterations are also conserved in our predicted models of five other kinetoplastid histone octamers ( Supplementary Figure S9B ).…”

Section: Resultsmentioning

confidence: 97%

Histone divergence in trypanosomes results in unique alterations to nucleosome structure

Deák

¹

,

Wapenaar

²

,

Sandoval

³

et al. 2023

Nucleic Acids Research

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Eukaryotes have a multitude of diverse mechanisms for organising and using their genomes, but the histones that make up chromatin are highly conserved. Unusually, histones from kinetoplastids are highly divergent. The structural and functional consequences of this variation are unknown. Here, we have biochemically and structurally characterised nucleosome core particles (NCPs) from the kinetoplastid parasite Trypanosoma brucei. A structure of the T. brucei NCP reveals that global histone architecture is conserved, but specific sequence alterations lead to distinct DNA and protein interaction interfaces. The T. brucei NCP is unstable and has weakened overall DNA binding. However, dramatic changes at the H2A-H2B interface introduce local reinforcement of DNA contacts. The T. brucei acidic patch has altered topology and is refractory to known binders, indicating that the nature of chromatin interactions in T. brucei may be unique. Overall, our results provide a detailed molecular basis for understanding evolutionary divergence in chromatin structure.

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“…5e,f). Of particular interest mutations (H2AE61A, H2AE92K and H2BE105A/E113A) within the nucleosome acidic patch, a hub of interaction for many nucleosome binding proteins 35,36 , profoundly impacted Dsup binding to mononucleosomes (EC 50 rel 22.8 nM WT to ND for each acid patch mutant; Fig. 5g).…”

Section: Dsup Binds Nucleosomes Via Multivalent Interactions With The...mentioning

confidence: 99%

Multivalent binding of the tardigrade Dsup protein to chromatin promotes yeast survival and longevity upon exposure to oxidative damage

Tyler,

Aguilar,

Arslanovic

et al. 2023

Preprint

2

0

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Tardigrades are remarkable in their ability to survive extreme environments. The damage suppressor (Dsup) protein is thought responsible for their extreme resistance to reactive oxygen species (ROS) generated by irradiation. Here we show that expression of Ramazzottius varieornatus Dsup in Saccharomyces cerevisiae reduces oxidative DNA damage and extends the lifespan of budding yeast exposed to chronic oxidative genotoxicity. This protection from ROS requires either the Dsup HMGN-like domain or sequences C-terminal to same. Dsup associates with no apparent bias across the yeast genome, using multiple modes of nucleosome binding; the HMGN-like region interacts with both the H2A/H2B acidic patch and H3/H4 histone tails, while the C-terminal region binds DNA. These findings give precedent for engineering an organism by physically shielding its genome to promote survival and longevity in the face of oxidative damage.

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Structural basis of paralog-specific KDM2A/B nucleosome recognition

Cited by 11 publications

References 55 publications

Histone divergence inTrypanosoma bruceiresults in unique alterations to nucleosome structure

Histone divergence inTrypanosoma bruceiresults in unique alterations to nucleosome structure

Histone divergence in trypanosomes results in unique alterations to nucleosome structure

Multivalent binding of the tardigrade Dsup protein to chromatin promotes yeast survival and longevity upon exposure to oxidative damage

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