scholarly journals Histone H4 acetylation required for chromatin decompaction during DNA replication

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Kun Ruan ◽  
Takaharu G. Yamamoto ◽  
Haruhiko Asakawa ◽  
Yuji Chikashige ◽  
Hiroshi Kimura ◽  
...  
Keyword(s):  
Dna Replication ◽  
Histone H4 ◽  
Histone H4 Acetylation

scholarly journals Protein kinase D1 phosphorylation of KAT7 enhances its protein stability and promotes replication licensing and cell proliferation

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Yao Liang ◽  
Yuanyuan Su ◽  
Chenzhong Xu ◽  
Na Zhang ◽  
Doudou Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Replication ◽  
Protein Kinase ◽  
Histone H4 ◽  
Replication Complex ◽  
Protein Kinase D1 ◽  
Defective Mutant ◽  
Histone H4 Acetylation

Abstract The histone acetyltransferase (HAT) KAT7/HBO1/MYST2 plays a crucial role in the pre-replication complex (pre-RC) formation, DNA replication and cell proliferation via acetylation of histone H4 and H3. In a search for protein kinase D1 (PKD1)-interacting proteins, we have identified KAT7 as a potential PKD1 substrate. We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation. Significantly, the phospho-defective mutant KAT7-Thr97/331A attenuates histone H4 acetylation levels, MCM2/6 loading on the chromatin, DNA replication and cell proliferation. Similarly, PKD1 knockdown decreases, whereas the constitutive active mutant PKD1-CA increases histone H4 acetylation levels and MCM2/6 loading on the chromatin. Overall, these results suggest that PKD1-mediated phosphorylation of KAT7 may be required for pre-RC formation and DNA replication.

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.

Euchromatic domains in plant chromosomes as revealed by H4 histone acetylation and early DNA replication

Genome ◽  
1999 ◽  
Vol 42 (2) ◽  
pp. 343-350 ◽  
Author(s):  
Boris Vyskot ◽  
Jiri Siroky ◽  
Renata Hladilova ◽  
Nikolai D Belyaev ◽  
Bryan M Turner
Keyword(s):  
Dna Replication ◽  
Sex Chromosomes ◽  
Silene Latifolia ◽  
Histone H4 ◽  
X Chromosomes ◽  
Plant Chromosomes ◽  
Histone H4 Acetylation ◽  
Immunofluorescence Labeling ◽  
Silene Species ◽  
Chromosome Regions

Using specific polyclonal antisera raised against acetylated isoforms of histone H4, we have analyzed their distribution in the dioecious plant Silene latifolia (syn.Melandrium album) possessing heteromorphic sex chromosomes. Our previous studies on this species have shown that one of the two X chromosomes in homogametic female cells is heavily methylated and late replicating, as a possible consequence of dosage compensation. Here we report that there are no detectable differences in intensity and distribution of H4 acetylation between these two X chromosomes. In S. latifolia only distal-subtelomeric chromosome regions, on both the sex chromosomes and autosomes, display strong signals of H4 acetylation at N-terminal lysines 5, 8, and 12. These acetylated domains correspond to the very early replicating distal chromosome regions as revealed by 5-bromodeoxyuridine pulses followed by the indirect immunofluorescence microscopy. The distribution of H4 acetylated at lysine 16 was uniform along the chromosomes. The unique distal-subtelomeric H4 acetylation signals were also observed in three other Silene species (S. vulgaris, S. pendula, andS. chalcedonica), but not in two non-related plant species tested (Allium cepa and Nicotiana tabacum). The presented data as well as our recent studies on the structure of S. latifolia chromosome ends indicate that Silene species possess the specific distal-subtelomeric location of euchromatin, gene-rich regions on chromosomes.Key words: histone H4 acetylation, DNA replication, euchromatin, immunofluorescence labeling, Silene spp.

scholarly journals Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

2007 ◽  
Vol 28 (1) ◽  
pp. 140-153 ◽  
Author(s):  
Masayoshi Iizuka ◽  
Olga F. Sarmento ◽  
Takao Sekiya ◽  
Heidi Scrable ◽  
C. David Allis ◽  
...  
Keyword(s):  
Dna Replication ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Stress Signaling ◽  
Dependent Manner ◽  
Histone H4 ◽  
Steroid Dependent ◽  
Histone H4 Acetylation ◽  
Replication Fork Arrest

ABSTRACT Hbo1 is a histone acetyltransferase (HAT) that is required for global histone H4 acetylation, steroid-dependent transcription, and chromatin loading of MCM2-7 during DNA replication licensing. It is the catalytic subunit of protein complexes that include ING and JADE proteins, growth regulatory factors and candidate tumor suppressors. These complexes are thought to act via tumor suppressor p53, but the molecular mechanisms and links between stress signaling and chromatin, are currently unknown. Here, we show that p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Two physiological stresses that stabilize p53, hyperosmotic shock and DNA replication fork arrest, also inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G1 phase specifically inhibits the loading of the MCM2-7 complex, providing an example of the chromatin output of this pathway. These results reveal a direct regulatory connection between p53-responsive stress signaling and Hbo1-dependent chromatin pathways.

scholarly journals CBIO-19. LOW GLOBAL HISTONE H4 ACETYLATION LEVELS REVEAL CANDIDATE QUIESCENT CELL POPULATIONS IN GLIOMA AND DISTINGUISH TUMORS BY GRADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii19-ii19
Author(s):  
Anca Mihalas ◽  
Heather Feldman ◽  
Anoop Patel ◽  
Patrick Paddison
Keyword(s):  
Cell Types ◽  
Strand Break ◽  
Cell Cycle Gene ◽  
Low Grade ◽  
Histone H4 ◽  
Current Standard ◽  
A Genome ◽  
Histone H4 Acetylation

Abstract Current standard of care therapy for glioblastoma (GBM) includes cytoreduction followed by ablative therapies that target rapidly dividing cell types. However, the presence of quiescent-like/G0 states, therefore, represents a natural reservoir of tumor cells that are resistant to current treatments. Quiescence or G0 phase is a reversible state of “stasis” cells enter in response to developmental or environmental cues. To gain insight into how glioblastoma cells might regulate G0-like states, we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) harboring a G0-reporter to identify genes that when inhibited trap GSCs in G0-like states. Among the top screen hits were members of the Tip60/KAT5 histone acetyltransferase complex, which targets both histones (e.g., H4) and non-histone proteins for acetylation. NuA4 functions as a transcriptional activator, whose activities are coordinated with MYC in certain contexts, and also participates in DNA double-strand break repair by facilitating chromatin opening. However, currently little is known about the roles for NuA4 complex in GBM biology. Through modeling KAT5 function in GSC in vitro cultures and in vivo tumors, we find that KAT5 inhibition causes cells to arrest in a G0-like state with high p27 levels, G1-phase DNA content, low protein synthesis rates, low rRNA rates, lower metabolic rate, suppression of cell cycle gene expression, and low histone H4 acetylation. Interestingly, partial inhibition of KAT5 activity slows highly aggressive tumor growth, while increasing p27hi H4-aclow populations. Remarkably, we that low grade gliomas have significantly higher H4-aclow subpopulations and generally lower H4-ac levels than aggressive grade IV tumors. Taken together, our results suggest that NuA4/KAT5 activity may play a key role in quiescence ingress/egress in glioma and that targeting its activity in high grade tumors may effectively “down grade” them, thus, increase patient survival.

scholarly journals Radiosensitization of Yeast Cells by Inhibition of Histone H4 Acetylation

2008 ◽  
Vol 170 (5) ◽  
pp. 618-627 ◽  
Author(s):  
Suisui Song ◽  
Kelly E. McCann ◽  
J. Martin Brown
Keyword(s):  
Yeast Cells ◽  
Histone H4 ◽  
Histone H4 Acetylation

scholarly journals Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

2013 ◽  
Vol 33 (16) ◽  
pp. 3286-3298 ◽  
Author(s):  
Zhongqi Ge ◽  
Devi Nair ◽  
Xiaoyan Guan ◽  
Neha Rastogi ◽  
Michael A. Freitas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Histone H3 ◽  
Model Organism ◽  
Strand Break ◽  
Chromatin Assembly ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Damage Response ◽  
A Site

The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH2-terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (γ-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling.

scholarly journals Activation Domain-Specific and General Transcription Stimulation by Native Histone Acetyltransferase Complexes

1999 ◽  
Vol 19 (1) ◽  
pp. 855-863 ◽  
Author(s):  
Keiko Ikeda ◽  
David J. Steger ◽  
Anton Eberharter ◽  
Jerry L. Workman
Keyword(s):  
Histone Acetyltransferase ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Saga Complex ◽  
Histone H4 ◽  
Activation Domain ◽  
Activation Domains ◽  
Nucleosomal Array ◽  
Histone H4 Acetylation

ABSTRACT Recent progress in identifying the catalytic subunits of histone acetyltransferase (HAT) complexes has implicated histone acetylation in the regulation of transcription. Here, we have analyzed the function of two native yeast HAT complexes, SAGA (Spt-Ada-Gcn5 Acetyltransferase) and NuA4 (nucleosome acetyltransferase of H4), in activating transcription from preassembled nucleosomal array templates in vitro. Each complex was tested for the ability to enhance transcription driven by GAL4 derivatives containing either acidic, glutamine-rich, or proline-rich activation domains. On nucleosomal array templates, the SAGA complex selectively stimulates transcription driven by the VP16 acidic activation domain in an acetyl coenzyme A-dependent manner. In contrast, the NuA4 complex facilitates transcription mediated by any of the activation domains tested if allowed to preacetylate the nucleosomal template, indicating a general stimulatory effect of histone H4 acetylation. However, when the extent of acetylation by NuA4 is limited, the complex also preferentially stimulates VP16-driven transcription. SAGA and NuA4 interact directly with the VP16 activation domain but not with a glutamine-rich or proline-rich activation domain. These data suggest that recruitment of the SAGA and NuA4 HAT complexes by the VP16 activation domain contributes to HAT-dependent activation. In addition, extensive H4/H2B acetylation by NuA4 leads to a general activation of transcription, which is independent of activator-NuA4 interactions.

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