scholarly journals The NuA4 Core Complex Acetylates Nucleosomal Histone H4 through a Double Recognition Mechanism

2016 ◽  
Vol 63 (6) ◽  
pp. 965-975 ◽  
Author(s):  
Peng Xu ◽  
Chengmin Li ◽  
Zhihong Chen ◽  
Shuanying Jiang ◽  
Shilong Fan ◽  
...  
Keyword(s):  
Histone H4 ◽  
Core Complex ◽  
Recognition Mechanism ◽  
Nucleosomal Histone

scholarly journals NuA4 Subunit Yng2 Function in Intra-S-Phase DNA Damage Response

2002 ◽  
Vol 22 (23) ◽  
pp. 8215-8225 ◽  
Author(s):  
John S. Choy ◽  
Stephen J. Kron
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Histone Acetylation ◽  
Trichostatin A ◽  
S Phase ◽  
Open Chromatin ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Nucleosomal Histone

ABSTRACT While regulated transcription requires acetylation of histone N-terminal tails to promote an open chromatin conformation, a similar role for histone acetylation in DNA replication and/or repair remains to be established. Cells lacking the NuA4 subunit Yng2 are viable but critically deficient for genome-wide nucleosomal histone H4 acetylation. We found that yng2 mutants are specifically sensitized to DNA damage in S phase induced by cdc8 or cdc9 mutations, hydroxyurea, camptothecin, or methylmethane sulfonate (MMS). In yng2, MMS treatment causes a persistent Mec1-dependent intra-S-phase checkpoint delay characterized by slow DNA repair. Restoring H4 acetylation with the histone deacetylase inhibitor trichostatin A promotes checkpoint recovery. In turn, mutants lacking the histone H3-specific acetyltransferase GCN5 are similarly sensitive to intra-S-phase DNA damage. The inviability of gcn5 yng2 double mutants suggests overlapping roles for H3 and H4 acetylation in DNA replication and repair. Paradoxically, haploid yng2 mutants do not tolerate mutations in genes important for nonhomologous end joining repair yet remain proficient for homologous recombination. Our results implicate nucleosomal histone acetylation in maintaining genomic integrity during chromosomal replication.

scholarly journals Structural basis of nucleosomal histone H4 lysine 20 methylation by SET8 methyltransferase

2021 ◽  
Vol 4 (4) ◽  
pp. e202000919
Author(s):  
Cheng-Han Ho ◽  
Yoshimasa Takizawa ◽  
Wataru Kobayashi ◽  
Yasuhiro Arimura ◽  
Hiroshi Kimura ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Essential Role ◽  
Histone H3 ◽  
Underlying Mechanism ◽  
Structural Basis ◽  
Histone H4 ◽  
Nucleosomal Histone

SET8 is solely responsible for histone H4 lysine-20 (H4K20) monomethylation, which preferentially occurs in nucleosomal H4. However, the underlying mechanism by which SET8 specifically promotes the H4K20 monomethylation in the nucleosome has not been elucidated. Here, we report the cryo-EM structures of the human SET8–nucleosome complexes with histone H3 and the centromeric H3 variant, CENP-A. Surprisingly, we found that the overall cryo-EM structures of the SET8–nucleosome complexes are substantially different from the previous crystal structure models. In the complexes with H3 and CENP-A nucleosomes, SET8 specifically binds the nucleosomal acidic patch via an arginine anchor, composed of the Arg188 and Arg192 residues. Mutational analyses revealed that the interaction between the SET8 arginine anchor and the nucleosomal acidic patch plays an essential role in the H4K20 monomethylation activity. These results provide the groundwork for understanding the mechanism by which SET8 specifically accomplishes the H4K20 monomethylation in the nucleosome.

scholarly journals Purification and Functional Characterization of SET8, a Nucleosomal Histone H4-Lysine 20-Specific Methyltransferase

2002 ◽  
Vol 12 (13) ◽  
pp. 1086-1099 ◽  
Author(s):  
Jia Fang ◽  
Qin Feng ◽  
Carrie S. Ketel ◽  
Hengbin Wang ◽  
Ru Cao ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Histone H4 ◽  
Nucleosomal Histone

scholarly journals Cryo-EM structure of the human Mixed Lineage Leukemia-1 complex bound to the nucleosome

2019 ◽  
Author(s):  
Sang Ho Park ◽  
Alex Ayoub ◽  
Young Tae Lee ◽  
Jing Xu ◽  
Hanseong Kim ◽  
...  
Keyword(s):  
Mixed Lineage Leukemia ◽  
Chromatin Binding ◽  
Histone H4 ◽  
Core Complex ◽  
Regulate Gene Expression ◽  
Histone Methyltransferases ◽  
Nucleosome Core ◽  
Nucleosomal Dna ◽  
Histone H3k4 ◽  
Methylation Activity

SUMMARYMixed Lineage Leukemia (MLL) family histone methyltransferases are the key enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanism by which the MLL complexes recognize histone H3K4 within the nucleosome core particle (NCP) remains unclear. Here, we report the single-particle cryo-electron microscopy (cryo-EM) structure of the human MLL1 core complex bound to the NCP. The MLL1 core complex anchors on the NCP through RbBP5 and ASH2L, which interacts extensively with nucleosomal DNA as well as the surface close to histone H4 N-terminal tail. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, allowing symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

scholarly journals Cryo-EM structure of the human MLL1 core complex bound to the nucleosome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sang Ho Park ◽  
Alex Ayoub ◽  
Young-Tae Lee ◽  
Jing Xu ◽  
Hanseong Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Histone H4 ◽  
Core Complex ◽  
Regulate Gene Expression ◽  
Histone Methyltransferases ◽  
Nucleosome Core ◽  
Nucleosome Core Particles ◽  
Nucleosomal Dna ◽  
Histone H3k4 ◽  
Methylation Activity

AbstractMixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. We show that the MLL1 core complex anchors to the NCP via the conserved RbBP5 and ASH2L, which interact extensively with nucleosomal DNA and the surface close to the N-terminal tail of histone H4. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, thereby facilitating symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

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