Abstract
H2A.Z is a histone H2A variant that contributes to transcriptional regulation, DNA damage response and limits heterochromatin spreading. In Saccharomyces cerevisiae, H2A.Z is deposited by the SWR-C complex, which relies on several histone chaperones including Nap1 and Chz1 to deliver H2A.Z-H2B dimers to SWR-C. However, the mechanisms by which Nap1 and Chz1 cooperate to bind H2A.Z and their contribution to H2A.Z deposition in chromatin is not well understood. Using structural modeling and molecular dynamics simulations, we identify a series of H2A.Z residues that form a chaperone-specific binding surface. Mutation of these residues revealed different surface requirements for Nap1 and Chz1 interaction with H2A.Z. Consistent with this result, we found that loss of Nap1 or Chz1 individually resulted in mild defects in H2A.Z deposition, but that deletion of both Nap1 and Chz1 resulted in a significant reduction of H2A.Z deposition at promoters and led to heterochromatin spreading. Together, our findings reveal unique H2A.Z surface dependences for Nap1 and Chz1 and a redundant role for these chaperones in H2A.Z deposition.
Highlights
Eukaryotic chromatin is regulated by multiple mechanisms that include post-translational histone modifications, ATP-dependent chromatin remodeling, and replacement of canonical histones with histone variants[1]
Using structural modeling and discrete molecular dynamic (DMD) simulations, we discovered specific residues of H2A.Z that are critical for interactions with either Chz[1] or Nap[1]
Constraint-driven Chz1-H2A.Z-H2B (CZB) structural ensemble generated by Discrete Molecular Dynamics simulations
Summary
Eukaryotic chromatin is regulated by multiple mechanisms that include post-translational histone modifications, ATP-dependent chromatin remodeling, and replacement of canonical histones with histone variants[1]. The major factor for regulated deposition of H2A.Z in chromatin in budding yeast is the SWR1 complex (SWR-C)[11]. SWR-C is an ATP-dependent chromatin-remodeling complex that recognizes the acidic surface on the H2A.Z-H2B dimer[12] to deposit it into chromatin. Histone chaperones Nap[1] and Chz[1] have been implicated to work in close association with SWR1 complex in the deposition of H2A.Z into chromatin[4]. Mutations in H2A.Z and/or deletion of both Nap[1] and Chz[1] lead to severe biological consequences such as decreased survival in the presence of genotoxic or transcriptional stressors and defects in H2A.Z deposition that result in heterochromatin spreading
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