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1.
Proc Natl Acad Sci U S A ; 121(21): e2405827121, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38748572

ABSTRACT

The RNA polymerase II (Pol II) elongation rate influences poly(A) site selection, with slow and fast Pol II derivatives causing upstream and downstream shifts, respectively, in poly(A) site utilization. In yeast, depletion of either of the histone chaperones FACT or Spt6 causes an upstream shift of poly(A) site use that strongly resembles the poly(A) profiles of slow Pol II mutant strains. Like slow Pol II mutant strains, FACT- and Spt6-depleted cells exhibit Pol II processivity defects, indicating that both Spt6 and FACT stimulate the Pol II elongation rate. Poly(A) profiles of some genes show atypical downstream shifts; this subset of genes overlaps well for FACT- or Spt6-depleted strains but is different from the atypical genes in Pol II speed mutant strains. In contrast, depletion of histone H3 or H4 causes a downstream shift of poly(A) sites for most genes, indicating that nucleosomes inhibit the Pol II elongation rate in vivo. Thus, chromatin-based control of the Pol II elongation rate is a potential mechanism, distinct from direct effects on the cleavage/polyadenylation machinery, to regulate alternative polyadenylation in response to genetic or environmental changes.


Subject(s)
Chromatin , Histones , Polyadenylation , RNA Polymerase II , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Transcriptional Elongation Factors , RNA Polymerase II/metabolism , RNA Polymerase II/genetics , Chromatin/metabolism , Chromatin/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae Proteins/genetics , Histones/metabolism , Transcriptional Elongation Factors/metabolism , Transcriptional Elongation Factors/genetics , Nucleosomes/metabolism , Nucleosomes/genetics , Transcription Elongation, Genetic , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Histone Chaperones/metabolism , Histone Chaperones/genetics , Poly A/metabolism
2.
Curr Opin Plant Biol ; 80: 102551, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38776573

ABSTRACT

Histone chaperones and histone variants play crucial roles in DNA replication, gene transcription, and DNA repair in eukaryotes. Histone chaperones reversibly promote nucleosome assembly and disassembly by incorporating or evicting histones and histone variants to modulate chromatin accessibility, thereby altering the chromatin states and modulating DNA-related biological processes. Cofactors assist histone chaperones to target specific chromatin regions to regulate the exchange of histones and histone variants. In this review, we summarize recent progress in the interplay between histone variants and chaperones in plants. We discuss the structural basis of chaperone-histone complexes and the mechanisms of their cooperation in regulating gene transcription and plant development.


Subject(s)
Histone Chaperones , Histones , Histones/metabolism , Histones/genetics , Histone Chaperones/metabolism , Histone Chaperones/genetics , Plants/metabolism , Plants/genetics , Chromatin/metabolism , Chromatin/genetics , Plant Proteins/metabolism , Plant Proteins/genetics , Molecular Chaperones/metabolism , Molecular Chaperones/genetics , Gene Expression Regulation, Plant , Nucleosomes/metabolism
3.
Int J Mol Med ; 53(5)2024 05.
Article in English | MEDLINE | ID: mdl-38577935

ABSTRACT

Histone chaperones serve a pivotal role in maintaining human physiological processes. They interact with histones in a stable manner, ensuring the accurate and efficient execution of DNA replication, repair and transcription. Retinoblastoma binding protein (RBBP)4 and RBBP7 represent a crucial pair of histone chaperones, which not only govern the molecular behavior of histones H3 and H4, but also participate in the functions of several protein complexes, such as polycomb repressive complex 2 and nucleosome remodeling and deacetylase, thereby regulating the cell cycle, histone modifications, DNA damage and cell fate. A strong association has been indicated between RBBP4/7 and some major human diseases, such as cancer, age­related memory loss and infectious diseases. The present review assesses the molecular mechanisms of RBBP4/7 in regulating cellular biological processes, and focuses on the variations in RBBP4/7 expression and their potential mechanisms in various human diseases, thus providing new insights for their diagnosis and treatment.


Subject(s)
Histones , Transcription Factors , Humans , Cell Cycle , Histone Chaperones/genetics , Histone Chaperones/chemistry , Histone Chaperones/metabolism , Histones/genetics , Histones/metabolism , Retinoblastoma-Binding Protein 4/chemistry , Retinoblastoma-Binding Protein 4/metabolism , Retinoblastoma-Binding Protein 7 , Transcription Factors/metabolism
4.
Cell Stress Chaperones ; 29(3): 392-403, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38608859

ABSTRACT

Histone H3/H4 chaperone anti-silencing function 1 (ASF1) is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the histone H3 lysine K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNA interference enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism, and that downregulation of the one-carbon metabolism component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Longevity , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Animals , Longevity/genetics , Carbon/metabolism , Molecular Chaperones/metabolism , Molecular Chaperones/genetics , Histones/metabolism , RNA Interference , Histone Chaperones/metabolism , Histone Chaperones/genetics , Epigenesis, Genetic
5.
Clin Genet ; 105(6): 683-685, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38511226

ABSTRACT

A case of a newborn with tetralogy of Fallot, corpus callosum hypoplasia, and phenotypic features similar to DiGeorge syndrome. Chromosomal microarray analysis did not reveal any alterations. Whole exome sequencing and Sanger sequencing identified a de novo variant in the HIRA gene resulting in the loss of the start codon.


Subject(s)
Cell Cycle Proteins , DiGeorge Syndrome , Histone Chaperones , Female , Humans , Infant, Newborn , Male , Agenesis of Corpus Callosum/genetics , Cell Cycle Proteins/genetics , DiGeorge Syndrome/genetics , DiGeorge Syndrome/pathology , Exome Sequencing , Histone Chaperones/genetics , Phenotype , Tetralogy of Fallot/genetics , Transcription Factors/genetics , Adult , Pedigree
6.
Blood ; 143(26): 2749-2762, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38498025

ABSTRACT

ABSTRACT: Identifying and targeting microenvironment-driven pathways that are active across acute myeloid leukemia (AML) genetic subtypes should allow the development of more broadly effective therapies. The proinflammatory cytokine interleukin-1ß (IL-1ß) is abundant in the AML microenvironment and promotes leukemic growth. Through RNA-sequencing analysis, we identify that IL-1ß-upregulated ASF1B (antisilencing function-1B), a histone chaperone, in AML progenitors compared with healthy progenitors. ASF1B, along with its paralogous protein ASF1A, recruits H3-H4 histones onto the replication fork during S-phase, a process regulated by Tousled-like kinase 1 and 2 (TLKs). Although ASF1s and TLKs are known to be overexpressed in multiple solid tumors and associated with poor prognosis, their functional roles in hematopoiesis and inflammation-driven leukemia remain unexplored. In this study, we identify that ASF1s and TLKs are overexpressed in multiple genetic subtypes of AML. We demonstrate that depletion of ASF1s significantly reduces leukemic cell growth in both in vitro and in vivo models using human cells. Using a murine model, we show that overexpression of ASF1B accelerates leukemia progression. Moreover, Asf1b or Tlk2 deletion delayed leukemia progression, whereas these proteins are dispensable for normal hematopoiesis. Through proteomics and phosphoproteomics analyses, we uncover that the TLK-ASF1 pathway promotes leukemogenesis by affecting the cell cycle and DNA damage pathways. Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.


Subject(s)
Cell Cycle Proteins , Disease Progression , Interleukin-1beta , Leukemia, Myeloid, Acute , Protein Serine-Threonine Kinases , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/genetics , Humans , Animals , Mice , Interleukin-1beta/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Molecular Chaperones/metabolism , Molecular Chaperones/genetics , Histone Chaperones/metabolism , Histone Chaperones/genetics , Histones/metabolism , Histones/genetics , Cell Line, Tumor , Serine-Arginine Splicing Factors/metabolism , Serine-Arginine Splicing Factors/genetics
7.
Genes Dev ; 38(3-4): 189-204, 2024 03 22.
Article in English | MEDLINE | ID: mdl-38479839

ABSTRACT

Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3-H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase ε, govern parental histone H3-H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using fission yeast heterochromatin inheritance systems that eliminate interference from initiation pathways, we show that a Mcm2 histone binding mutation severely disrupts heterochromatin inheritance, while mutations in Dpb3/4 cause only moderate defects. Surprisingly, simultaneous mutations of Mcm2 and Dpb3/4 stabilize heterochromatin inheritance. eSPAN (enrichment and sequencing of protein-associated nascent DNA) analyses confirmed the conservation of Mcm2 and Dpb3/4 functions in parental histone H3-H4 segregation, with their combined absence showing a more symmetric distribution of parental histone H3-H4 than either single mutation alone. Furthermore, the FACT histone chaperone regulates parental histone transfer to both strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone H3-H4 density and faithful heterochromatin inheritance. These results underscore the importance of both symmetric distribution of parental histones and their density at daughter strands for epigenetic inheritance and unveil distinctive properties of parental histone chaperones during DNA replication.


Subject(s)
Histones , Schizosaccharomyces , Histones/metabolism , Histone Chaperones/genetics , Histone Chaperones/metabolism , Heterochromatin/genetics , DNA Replication/genetics , DNA/metabolism , Schizosaccharomyces/genetics , Schizosaccharomyces/metabolism , Epigenesis, Genetic
8.
Genetics ; 226(4)2024 04 03.
Article in English | MEDLINE | ID: mdl-38407959

ABSTRACT

The disruption of chromatin structure can result in transcription initiation from cryptic promoters within gene bodies. While the passage of RNA polymerase II is a well-characterized chromatin-disrupting force, numerous factors, including histone chaperones, normally stabilize chromatin on transcribed genes, thereby repressing cryptic transcription. DNA replication, which employs a partially overlapping set of histone chaperones, is also inherently disruptive to chromatin, but a role for DNA replication in cryptic transcription has never been examined. In this study, we tested the hypothesis that, in the absence of chromatin-stabilizing factors, DNA replication can promote cryptic transcription in Saccharomyces cerevisiae. Using a novel fluorescent reporter assay, we show that multiple factors, including Asf1, CAF-1, Rtt106, Spt6, and FACT, block transcription from a cryptic promoter, but are entirely or partially dispensable in G1-arrested cells, suggesting a requirement for DNA replication in chromatin disruption. Collectively, these results demonstrate that transcription fidelity is dependent on numerous factors that function to assemble chromatin on nascent DNA.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Histones/metabolism , Nuclear Proteins/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Transcription, Genetic , Chromatin/genetics , Histone Chaperones/genetics , DNA , Molecular Chaperones/metabolism
9.
Cells ; 13(3)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38334665

ABSTRACT

HIRIP3 is a mammalian protein homologous to the yeast H2A.Z deposition chaperone Chz1. However, the structural basis underlying Chz's binding preference for H2A.Z over H2A, as well as the mechanism through which Chz1 modulates histone deposition or replacement, remains enigmatic. In this study, we aimed to characterize the function of HIRIP3 and to identify its interacting partners in HeLa cells. Our findings reveal that HIRIP3 is specifically associated in vivo with H2A-H2B dimers and CK2 kinase. While bacterially expressed HIRIP3 exhibited a similar binding affinity towards H2A and H2A.Z, the associated CK2 kinase showed a notable preference for H2A phosphorylation at serine 1. The recombinant HIRIP3 physically interacted with the H2A αC helix through an extended CHZ domain and played a crucial role in depositing the canonical core histones onto naked DNA. Our results demonstrate that mammalian HIRIP3 acts as an H2A histone chaperone, assisting in its selective phosphorylation by Ck2 kinase at serine 1 and facilitating its deposition onto chromatin.


Subject(s)
Histone Chaperones , Histones , Animals , Humans , HeLa Cells , Histone Chaperones/genetics , Histones/metabolism , Mammals/metabolism , Molecular Chaperones/metabolism , Saccharomyces cerevisiae/metabolism , Serine , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism
10.
Nat Struct Mol Biol ; 31(3): 523-535, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38238586

ABSTRACT

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find that spt-2 mutants have increased chromatin accessibility at a subset of these loci. We also show that SPT2 influences chromatin structure and controls the levels of soluble and chromatin-bound H3.3 in human cells. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.


Subject(s)
DNA-Binding Proteins , Histone Chaperones , Animals , Humans , Histone Chaperones/genetics , Histone Chaperones/metabolism , DNA-Binding Proteins/metabolism , Histones/metabolism , Chromatin/metabolism , Nucleosomes/metabolism , Saccharomyces cerevisiae/metabolism
11.
Exp Mol Med ; 56(2): 251-263, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38297159

ABSTRACT

H3.3, the most common replacement variant for histone H3, has emerged as an important player in chromatin dynamics for controlling gene expression and genome integrity. While replicative variants H3.1 and H3.2 are primarily incorporated into nucleosomes during DNA synthesis, H3.3 is under the control of H3.3-specific histone chaperones for spatiotemporal incorporation throughout the cell cycle. Over the years, there has been progress in understanding the mechanisms by which H3.3 affects domain structure and function. Furthermore, H3.3 distribution and relative abundance profoundly impact cellular identity and plasticity during normal development and pathogenesis. Recurrent mutations in H3.3 and its chaperones have been identified in neoplastic transformation and developmental disorders, providing new insights into chromatin biology and disease. Here, we review recent findings emphasizing how two distinct histone chaperones, HIRA and DAXX, take part in the spatial and temporal distribution of H3.3 in different chromatin domains and ultimately achieve dynamic control of chromatin organization and function. Elucidating the H3.3 deposition pathways from the available histone pool will open new avenues for understanding the mechanisms by which H3.3 epigenetically regulates gene expression and its impact on cellular integrity and pathogenesis.


Subject(s)
Cell Cycle Proteins , Chromatin , Co-Repressor Proteins , Histones , Molecular Chaperones , Transcription Factors , Cell Cycle , Cell Division , Chromatin/genetics , Histone Chaperones/genetics , Humans , Molecular Chaperones/genetics , Co-Repressor Proteins/genetics , Transcription Factors/genetics , Cell Cycle Proteins/genetics
12.
Mol Cell ; 84(4): 791-801.e6, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38262410

ABSTRACT

In S phase, duplicating and assembling the whole genome into chromatin requires upregulation of replicative histone gene expression. Here, we explored how histone chaperones control histone production in human cells to ensure a proper link with chromatin assembly. Depletion of the ASF1 chaperone specifically decreases the pool of replicative histones both at the protein and RNA levels. The decrease in their overall expression, revealed by total RNA sequencing (RNA-seq), contrasted with the increase in nascent/newly synthesized RNAs observed by 4sU-labeled RNA-seq. Further inspection of replicative histone RNAs showed a 3' end processing defect with an increase of pre-mRNAs/unprocessed transcripts likely targeted to degradation. Collectively, these data argue for a production defect of replicative histone RNAs in ASF1-depleted cells. We discuss how this regulation of replicative histone RNA metabolism by ASF1 as a "chaperone checkpoint" fine-tunes the histone dosage to avoid unbalanced situations deleterious for cell survival.


Subject(s)
Histones , Saccharomyces cerevisiae Proteins , Humans , Histones/genetics , Histones/metabolism , Histone Chaperones/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , DNA Replication , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , RNA/genetics , Saccharomyces cerevisiae Proteins/metabolism
13.
FEBS Lett ; 598(2): 187-198, 2024 01.
Article in English | MEDLINE | ID: mdl-38058218

ABSTRACT

Nucleoplasmin (NPM) histone chaperones regulate distinct processes in the nucleus and nucleolus. While intrinsically disordered regions (IDRs) are hallmarks of NPMs, it is not clear whether all NPM functions require these unstructured features. We assessed the importance of IDRs in a yeast NPM-like protein and found that regulation of rDNA copy number and genetic interactions with the nucleolar RNA surveillance machinery require the highly conserved FKBP prolyl isomerase domain, but not the NPM domain or IDRs. By contrast, transcriptional repression in the nucleus requires IDRs. Furthermore, multiple lysines in polyacidic serine/lysine motifs of IDRs are required for both lysine polyphosphorylation and NPM-mediated transcriptional repression. These results demonstrate that this NPM-like protein relies on IDRs only for some of its chromatin-related functions.


Subject(s)
Histone Chaperones , Lysine , Histone Chaperones/genetics , Histone Chaperones/metabolism , Nucleoplasmins/metabolism , Lysine/metabolism , Chromatin/genetics , Chromatin/metabolism , Cell Nucleolus/genetics , Cell Nucleolus/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism
14.
J Biol Chem ; 300(1): 105538, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38072046

ABSTRACT

Histone chaperone FACT (facilitates chromatin transcription) is well known to promote chromatin recovery during transcription. However, the mechanism how FACT regulates genome-wide chromatin accessibility and transcription factor binding has not been fully elucidated. Through loss-of-function studies, we show here that FACT component Ssrp1 is required for DNA replication and DNA damage repair and is also essential for progression of cell phase transition and cell proliferation in mouse embryonic fibroblast cells. On the molecular level, absence of the Ssrp1 leads to increased chromatin accessibility, enhanced CTCF binding, and a remarkable change in dynamic range of gene expression. Our study thus unequivocally uncovers a unique mechanism by which FACT complex regulates transcription by coordinating genome-wide chromatin accessibility and CTCF binding.


Subject(s)
CCCTC-Binding Factor , Chromatin , DNA-Binding Proteins , Gene Expression Regulation , High Mobility Group Proteins , Histone Chaperones , Animals , Mice , CCCTC-Binding Factor/genetics , CCCTC-Binding Factor/metabolism , Chromatin/genetics , DNA Replication , Histone Chaperones/genetics , DNA-Binding Proteins/genetics , High Mobility Group Proteins/genetics , NIH 3T3 Cells , DNA Repair
15.
mBio ; 15(1): e0289623, 2024 Jan 16.
Article in English | MEDLINE | ID: mdl-38112417

ABSTRACT

IMPORTANCE: Histone chaperones are proteins that are involved in nucleosome assembly and disassembly and can therefore influence all DNA-dependent processes including transcription, DNA replication, and repair. ASF1 is a histone chaperone that is conserved throughout eukaryotes. In contrast to most other multicellular organisms, a deletion mutant of asf1 in the fungus Sordaria macrospora is viable; however, the mutant is sterile. In this study, we could show that the histone-binding ability of ASF1 is required for fertility in S. macrospora, whereas the function of ASF1 in maintenance of genome stability does not require histone binding. We also showed that the histone modifications H3K27me3 and H3K56ac are misregulated in the Δasf1 mutant. Furthermore, we identified a large duplication on chromosome 2 of the mutant strain that is genetically linked to the Δasf1 allele present on chromosome 6, suggesting that viability of the mutant might depend on the presence of the duplicated region.


Subject(s)
Histones , Sordariales , Histones/genetics , Histones/metabolism , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Histone Chaperones/genetics , Sordariales/genetics , Sordariales/metabolism , Genomic Instability , Cell Cycle Proteins/genetics
16.
J Biol Chem ; 300(1): 105584, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38141761

ABSTRACT

Protein phosphatase 2A (PP2A) is an essential tumor suppressor, with its activity often hindered in cancer cells by endogenous PP2A inhibitory proteins like SE translocation (SET). SET/PP2A axis plays a pivotal role in the colony-formation ability of cancer cells and the stabilization of c-Myc and E2F1 proteins implicated in this process. However, in osteosarcoma cell line HOS, SET knock-down (KD) suppresses the colony-formation ability without affecting c-Myc and E2F1. This study aimed to unravel the molecular mechanism through which SET enhances the colony-formation ability of HOS cells and determine if it is generalized to other cancer cells. Transcriptome analysis unveiled that SET KD suppressed mTORC1 signaling. SET KD inhibited Akt phosphorylation, an upstream kinase for mTORC1. PP2A inhibitor blocked SET KD-mediated decrease in phosphorylation of Akt and a mTORC1 substrate p70S6K. A constitutively active Akt restored decreased colony-formation ability by SET KD, indicating the SET/PP2A/Akt/mTORC1 axis. Additionally, enrichment analysis highlighted that Bmi-1, a polycomb group protein, is affected by SET KD. SET KD decreased Bmi-1 protein by Akt inhibition but not by mTORC1 inhibition, and exogenous Bmi-1 expression rescued the reduced colony formation by SET KD. Four out of eight cancer cell lines exhibited decreased Bmi-1 by SET KD. Further analysis of these cell lines revealed that Myc activity plays a role in SET KD-mediated Bmi-1 degradation. These findings provide new insights into the molecular mechanism of SET-regulated colony-formation ability, which involved Akt-mediated activation of mTORC1/p70S6K and Bmi-1 signaling.


Subject(s)
DNA-Binding Proteins , Enzyme Inhibitors , Histone Chaperones , Mechanistic Target of Rapamycin Complex 1 , Neoplasms , Polycomb Repressive Complex 1 , Protein Phosphatase 2 , Proto-Oncogene Proteins c-akt , Humans , Enzyme Inhibitors/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Phosphorylation , Polycomb Repressive Complex 1/metabolism , Protein Phosphatase 2/antagonists & inhibitors , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , TOR Serine-Threonine Kinases/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Histone Chaperones/deficiency , Histone Chaperones/genetics , Histone Chaperones/metabolism , Signal Transduction , Enzyme Activation , Cell Line, Tumor
17.
Nucleic Acids Res ; 51(21): 11549-11567, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-37850662

ABSTRACT

Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks. Intriguingly, deletion of the Spt16-N domain impairs parental histone recycling, with a more pronounced defect observed on the lagging strand. Mechanistically, the Spt16-N domain interacts with the replicative helicase MCM2-7 and facilitates the formation of a ternary complex involving FACT, histone H3/H4 and Mcm2 histone binding domain, critical for the recycling and transfer of parental histones to lagging strands. Lack of the Spt16-N domain weakens the FACT-MCM interaction and reduces parental histone recycling. We propose that the Spt16-N domain acts as a protein-protein interaction module, enabling FACT to function as a shuttle chaperone in collaboration with Mcm2 and potentially other replisome components for efficient local parental histone recycling and inheritance.


Subject(s)
Histones , Saccharomyces cerevisiae Proteins , Transcriptional Elongation Factors , Chromatin/genetics , DNA Helicases/genetics , Histone Chaperones/genetics , Histone Chaperones/metabolism , Histones/metabolism , Molecular Chaperones/genetics , Nucleosomes/genetics , Saccharomyces cerevisiae Proteins/metabolism , Transcriptional Elongation Factors/metabolism , Multiprotein Complexes/metabolism
18.
Mol Cell ; 83(21): 3773-3786, 2023 Nov 02.
Article in English | MEDLINE | ID: mdl-37734377

ABSTRACT

Histone variants provide versatility in the basic unit of chromatin, helping to define dynamic landscapes and cell fates. Maintaining genome integrity is paramount for the cell, and it is intimately linked with chromatin dynamics, assembly, and disassembly during DNA transactions such as replication, repair, recombination, and transcription. In this review, we focus on the family of H3 variants and their dynamics in space and time during the cell cycle. We review the distinct H3 variants' specific features along with their escort partners, the histone chaperones, compiled across different species to discuss their distinct importance considering evolution. We place H3 dynamics at different times during the cell cycle with the possible consequences for genome stability. Finally, we examine how their mutation and alteration impact disease. The emerging picture stresses key parameters in H3 dynamics to reflect on how when they are perturbed, they become a source of stress for genome integrity.


Subject(s)
Chromatin , Histones , Histones/genetics , Histones/metabolism , Chromatin/genetics , Cell Cycle/genetics , DNA , Histone Chaperones/genetics
19.
Toxicol Appl Pharmacol ; 477: 116697, 2023 10 15.
Article in English | MEDLINE | ID: mdl-37734572

ABSTRACT

Arsenic exposure is associated with an increased risk of many cancers, and epigenetic mechanisms play a crucial role in arsenic-mediated carcinogenesis. Our previous studies have shown that arsenic exposure induces polyadenylation of H3.1 mRNA and inhibits the deposition of H3.3 at critical gene regulatory elements. However, the precise underling mechanisms are not yet understood. To characterize the factors governing arsenic-induced inhibition of H3.3 assembly through H3.1 mRNA polyadenylation, we utilized mass spectrometry to identify the proteins, especially histone chaperones, with reduced binding affinity to H3.3 under conditions of arsenic exposure and polyadenylated H3.1 mRNA overexpression. Our findings reveal that the interaction between H3.3 and the histone chaperon protein MCM2 is diminished by both polyadenylated H3.1 mRNA overexpression and arsenic treatment in human lung epithelial BEAS-2B cells. The increased binding of MCM2 to H3.1, resulting from elevated H3.1 protein levels, appears to contribute to the reduced availability of MCM2 for H3.3. To further investigate the role of MCM2 in H3.3 deposition during arsenic exposure and H3.1 mRNA polyadenylation, we overexpressed MCM2 in BEAS-2B cells overexpressing polyadenylated H3.1 or exposed to arsenic. Our results demonstrate that MCM2 overexpression attenuates H3.3 depletion at several genomic loci, suggesting its involvement in the arsenic-induced displacement of H3.3 mediated by H3.1 mRNA polyadenylation. These findings suggest that changes in the association between histone chaperone MCM2 and H3.3 due to polyadenylation of H3.1 mRNA may play a pivotal role in arsenic-induced carcinogenesis.


Subject(s)
Arsenic , Humans , Arsenic/toxicity , Arsenic/chemistry , Histone Chaperones/genetics , Carcinogenesis , Genomics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Minichromosome Maintenance Complex Component 2/chemistry , Minichromosome Maintenance Complex Component 2/metabolism
20.
Cell Cycle ; 22(17): 1921-1936, 2023 09.
Article in English | MEDLINE | ID: mdl-37635373

ABSTRACT

Quiescence (G0) is a reversible non-dividing state that facilitates cellular survival in adverse conditions. Here, we demonstrate that the HIRA histone chaperone complex is required for the reversibility and longevity of nitrogen starvation-induced quiescence in Schizosaccharomyces pombe. The HIRA protein, Hip1 is not required for entry into G0 or the induction of autophagy. Although hip1Δ cells retain metabolic activity in G0, they rapidly lose the ability to resume proliferation. After a short period in G0 (1 day), hip1Δ mutants can resume cell growth in response to the restoration of a nitrogen source but do not efficiently reenter the vegetative cell cycle. This correlates with a failure to induce the expression of MBF transcription factor-dependent genes that are critical for S phase. In addition, hip1Δ G0 cells rapidly progress to a senescent state in which they can no longer re-initiate growth following nitrogen source restoration. Analysis of a conditional hip1 allele is consistent with these findings and indicates that HIRA is required for efficient exit from quiescence and prevents an irreversible cell cycle arrest.


Subject(s)
Schizosaccharomyces pombe Proteins , Schizosaccharomyces , Schizosaccharomyces/metabolism , Schizosaccharomyces pombe Proteins/genetics , Schizosaccharomyces pombe Proteins/metabolism , Histone Chaperones/genetics , Cell Division , Cell Cycle Proteins/metabolism , Nitrogen/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
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