scholarly journals SIR2-Induced Inviability Is Suppressed by Histone H4 Overexpression

Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 973-976 ◽  
Author(s):  
Mirela Matecic ◽  
Shelagh Stuart ◽  
Scott G Holmes
Keyword(s):  
Specific Interaction ◽  
Histone H3 ◽  
Yeast Cells ◽  
High Expression ◽  
Histone H4

Abstract We have identified histone H4 as a high-expression suppressor of Sir2-induced inviability in yeast cells. Overexpression of histone H3 does not suppress Sir2-induced lethality, nor does overexpression of histone H4 alleles associated with silencing defects. These results suggest a direct and specific interaction between Sir2 and H4 in the silencing mechanism.

scholarly journals DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wendan Ren ◽  
Huitao Fan ◽  
Sara A. Grimm ◽  
Jae Jin Kim ◽  
Linhui Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Histone H3 ◽  
Genomic Stability ◽  
Mammalian Genome ◽  
Dna Methyltransferase 1 ◽  
Chromatin Modifications ◽  
Direct Link ◽  
Histone H4 ◽  
Radiation Induced

AbstractDNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

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 Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation

Science ◽  
2021 ◽  
Vol 371 (6527) ◽  
pp. eabc6663
Author(s):  
Marco Igor Valencia-Sánchez ◽  
Pablo De Ioannes ◽  
Miao Wang ◽  
David M. Truong ◽  
Rachel Lee ◽  
...  
Keyword(s):  
Histone H3 ◽  
Histone H4 ◽  
Histone H2b ◽  
Epigenetic State ◽  
Optimal Maintenance ◽  
H4k16 Acetylation ◽  
H3k79 Methylation ◽  
Regulate Gene

Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.

scholarly journals Histone H4 H75E mutation attenuates global genomic and Rad26-independent transcription-coupled nucleotide excision repair

2019 ◽  
Vol 47 (14) ◽  
pp. 7392-7401 ◽  
Author(s):  
Kathiresan Selvam ◽  
Sheikh Arafatur Rahman ◽  
Shisheng Li
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Histone H3 ◽  
Chromatin Accessibility ◽  
Dna Lesions ◽  
Histone H4 ◽  
Uv Sensitivity ◽  
Nucleotide Excision ◽  
Histone Octamers ◽  
Dna Silencing

Abstract Nucleotide excision repair (NER) consists of global genomic NER (GG-NER) and transcription coupled NER (TC-NER) subpathways. In eukaryotic cells, genomic DNA is wrapped around histone octamers (an H3–H4 tetramer and two H2A–H2B dimers) to form nucleosomes, which are well known to profoundly inhibit the access of NER proteins. Through unbiased screening of histone H4 residues in the nucleosomal LRS (loss of ribosomal DNA-silencing) domain, we identified 24 mutations that enhance or decrease UV sensitivity of Saccharomyces cerevisiae cells. The histone H4 H75E mutation, which is largely embedded in the nucleosome and interacts with histone H2B, significantly attenuates GG-NER and Rad26-independent TC-NER but does not affect TC-NER in the presence of Rad26. All the other histone H4 mutations, except for T73F and T73Y that mildly attenuate GG-NER, do not substantially affect GG-NER or TC-NER. The attenuation of GG-NER and Rad26-independent TC-NER by the H4H75E mutation is not due to decreased chromatin accessibility, impaired methylation of histone H3 K79 that is at the center of the LRS domain, or lowered expression of NER proteins. Instead, the attenuation is at least in part due to impaired recruitment of Rad4, the key lesion recognition and verification protein, to chromatin following induction of DNA lesions.

scholarly journals Interactions of Surfactant Proteins A and D with Saccharomyces cerevisiae and Aspergillus fumigatus

2001 ◽  
Vol 69 (4) ◽  
pp. 2037-2044 ◽  
Author(s):  
Martin J. Allen ◽  
Dennis R. Voelker ◽  
Robert J. Mason
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Aspergillus Fumigatus ◽  
Cell Walls ◽  
Specific Interaction ◽  
Surfactant Proteins ◽  
Yeast Cells ◽  
Calcium Dependent ◽  
Before And After ◽  
Carbohydrate Polymer ◽  
Defense Molecules

ABSTRACT Surfactant proteins A (SP-A) and D (SP-D) are members of the collectin family of calcium-dependent lectins and are important pulmonary host defense molecules. Human SP-A and SP-D and rat SP-D bind to Aspergillus fumigatus conidia, but the ligand remains unidentified. To identify a fungal ligand for SP-A and/or SP-D, we examined the interactions of the proteins with Saccharomyces cerevisiae. SP-D but not SP-A bound yeast cells, and EDTA inhibited the binding. SP-D also aggregated yeast cells and isolated yeast cell walls. Treating yeast cells to remove cell wall mannoprotein did not reduce SP-D binding, and SP-D failed to aggregate chitin. However, SP-D aggregated yeast glucan before and after treatment with a β(1→3)-glucanase, suggesting a specific interaction between the collectin and β(1→6)-glucan. In support of this idea, SP-D-induced yeast aggregation was strongly inhibited by pustulan [a β(1→6)-linked glucose homopolymer] but was not inhibited by laminarin [a β(1→3)-linked glucose homopolymer]. Additionally, pustulan but not laminarin strongly inhibited SP-D binding to A. fumigatus. The pustulan concentration for 50% inhibition of SP-D binding to A. fumigatus is 1.0 ± 0.3 μM glucose equivalents. Finally, SP-D showed reduced binding to the β(1→6)-glucan-deficient kre6 yeast mutant. Taken together, these observations demonstrate that β(1→6)-glucan is an important fungal ligand for SP-D and that glycosidic bond patterns alone can determine if an extended carbohydrate polymer is recognized by SP-D.

High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma

2012 ◽  
Vol 43 (9) ◽  
pp. 1425-1435 ◽  
Author(s):  
Chuanchao He ◽  
Junyao Xu ◽  
Jianlong Zhang ◽  
Dan Xie ◽  
Hua Ye ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Histone H3 ◽  
High Expression

scholarly journals Global Replication-Independent Histone H4 Exchange in Budding Yeast

2006 ◽  
Vol 5 (10) ◽  
pp. 1780-1787 ◽  
Author(s):  
Jeffrey Linger ◽  
Jessica K. Tyler
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Replication ◽  
Budding Yeast ◽  
Histone H3 ◽  
Eukaryotic Genome ◽  
Histone H4 ◽  
Histone Proteins ◽  
Dynamic Exchange ◽  
Histone Exchange

ABSTRACT The eukaryotic genome is packaged together with histone proteins into chromatin following DNA replication. Recent studies have shown that histones can also be assembled into chromatin independently of DNA replication and that this dynamic exchange of histones may be biased toward sites undergoing transcription. Here we show that epitope-tagged histone H4 can be incorporated into nucleosomes throughout the budding yeast (Saccharomyces cerevisiae) genome regardless of the phase of the cell cycle, the transcriptional status, or silencing of the region. Direct comparisons reveal that the amount of histone incorporation that occurs in G1-arrested cells is similar to that occurring in cells undergoing DNA replication. Additionally, we show that this histone incorporation is not dependent on the histone H3/H4 chaperones CAF-1, Asf1, and Hir1 individually. This study demonstrates that DNA replication and transcription are not necessary prerequisites for histone exchange in budding yeast, indicating that chromatin is more dynamic than previously thought.

Baseline Nucleophosmin Status in Mutated(M) Versus Unmutated (U) Immunoglobulin B-CLL Is a Nuclear Reflection of Different Signal Transduction Physiology.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5005-5005
Author(s):  
Jerina Boelens ◽  
Wim Van den Berghe ◽  
Guy Haegeman ◽  
Ann Janssens ◽  
Jan Philippe ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Histone H3 ◽  
Routine Practice ◽  
Histone H4 ◽  
Total Histone ◽  
Environmental Signals ◽  
Erk Activation ◽  
Erk Phosphorylation ◽  
The Difference

Abstract Aim: The difference in prognosis between B-CLL patients with (M) and wihout (U) somatic hypermutations of the immunoglobulin genes has led to a search for surrogate markers in routine practice. cDNA-Microarray differentiation between M and U led to further analysis of Zap-70, fibromodulin and LPLase, all of which succesfully discriminate the majority of M vs U.. In 1 of 2 proteomic studies searching the difference between M and U B-CLL, nucleophosmin came out as uniformly absent in 6 U patients and present in all 6 with M B-CLL. Nucleophosmin is a nucleolar non-ribosomal protein, associated with cellular proliferation. It is implicated in carcinogenesis as a differentiation blocker in K562 myeloid leukemias where its degradation from a 35 to a 21 kD form accompanies phorbol ester induced differentiation. In K562 this degradation is dependent on P-Erk-translocation to the nucleus that by itself depends on prolonged Erk-activation. We have recently demonstrated that SDF-1, an important microenvironment factor in B-CLL, is capable of inducing prolonged Erk-activation in Zap-70+ but not in Zap-70- B-CLL cells in vitro. This prompted us to study the unstimulated expression of nucleophosmin and other nuclear proteins by Westen blot in 16 patients with B-CLL. Methods: Histones and other alkalic proteins were extracted from the nuclei (pellet fraction) upon treatment with 0.4 M HCl. Following precipitation in acetone, histones and proteins were resuspended in sample buffer and separated by SDS PAGE or acid urea gel electrophoresis. Subsequently, the proteins were electrotransferred to a nitrocellulose membrane. Western blot analysis was performed against nucleophosmin, histone H3 or H4, and final signal detection was revealed by enhanced chemiluminescence reaction. Results: The 35 kD nucleophosmin signal was uniformly expressed in all samples and related to total histone content, irrespective of mutation status, cytogenetics and stage of disease. However, a minor band at 21 kD reflecting degradation was present in 6/6 patients with U B-CLL and absent in 8/10 with M B-CLL. Pan-histone H3 and H4 antibodies revealed similar banding patterns for histone H3 in all patients, but the presence of a heavier (probably ubiquinated) double band for histone H4 in some. This ubiquinated fraction was important in 7/16, faint in 5/16 and absent in 4/16. Morphology was atypical in 4/7 with an important fraction, and typical in all others. 5/7 with important bands and 4/5 with faint bands were M B-CLL against only 1 out of 4 in the group with absence of ubiquitination bands. Discussion: In contrast to previous proteomic studies, we found the 35 kD form of nucleophosmin present in both M and U B-CLL. However, nucleophosmin metabolisation to the 21 kD form is observed preferentially in the U B-CLL. The increased baseline degradation of nucleophosmin in 6/6 U B-CLL all of whom are Zap-70+ can be explained as a downstream nuclear signal from constitutive increased Erk-phosphorylation upon environmental signals in Zap-70+ B-CLL.

Clinical Significance of WDR5 High Expression and Its Effect on Tumorigenesis in Adult Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3657-3657
Author(s):  
Zheng Ge ◽  
Evelyn Song ◽  
Jianyong Li ◽  
Sinisa Dovat ◽  
Chunhua Song
Keyword(s):  
Cell Proliferation ◽  
Conflicts Of Interest ◽  
Function Analysis ◽  
Lymphoblastic Leukemia ◽  
Histone H3 ◽  
Leukemia Cell ◽  
Annexin V ◽  
High Expression ◽  
Leukemic Cells ◽  
Methyltransferase Activity

Abstract Background: Mixed-lineage leukemia (MLL) functions within the context of a large multiprotein complex including MLL, WDR5, RbBP5, and ASH2L that is required for maximal enzymatic activity. Each component is required for full histone H3 trimethyl Lysine 4 (H3K4me3) methyltransferase activity of the complex. The structure-function analysis shows that WDR5 mediates interaction between the MLL catalytic unit and the core complex, as well as the histone H3 substrate. Recently it is found that blocking MLL1-WDR5 interaction by an inhibitor could result in the complex disassembly, inhibition methyltransferase activity and suppression of proliferation of leukemia cells. Despite our growing knowledge about MLL1 fusion proteins and leukemia, very little is known about the role of WDR5 in leukemia. Methods: The WDR5 expression was determined by qPCR in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. The genome-wide binding profiling of WDR5 and H3K4me3 was obtained by ChIP-seq. The effect of WDR5 on its target gene expression, cell proliferation and apoptosis was observed by qPCR, WST-1 cell proliferation assay and Annexin V-PE staining following the flow cytometry analysis, respectively, in leukemic cells with WDR5 shRNA knockdown Results: WDR5 expression is significantly increased in adult ALL and AML compared to that of normal bone marrow control. WDR5 high expression is associated with high risk factors in the patients. Also, its high expression is associated with MLL1 high expression; particularly the patients with WDR5 high expression plus MLL1 high expression has poor complete remission (CR) rate. We further identified the global genomic binding of WDR5 in RS4:11 ALL and THP-1 AML cells by ChIP-seq and detected more than 2000 binding peaks in the two leukemia cell lines. We also examined global H3K4me3 peaks, analyzed the correlation of WDR5 peaks with H3K4me3 peaks and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppressed the cell proliferation, induced apoptosis, inhibited the expression of WDR5 targets on oncogenesis and anti-apoptosis, blocked the H3K4me3 enrichment on the promoter of these targets. We also observed the positive correlation of WDR5 expression with its targets in B-ALL and AML cohort. Conclusion: WDR5 has oncogenic effect and WDR5-mediated H3K4 methylation plays important role in the leukemogenesis Disclosures No relevant conflicts of interest to declare.

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