scholarly journals Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)

2012 ◽  
Vol 209 (13) ◽  
pp. 2323-2330 ◽  
Author(s):  
Jana Pachlopnik Schmid ◽  
Roxane Lemoine ◽  
Nadine Nehme ◽  
Valéry Cormier-Daire ◽  
Patrick Revy ◽  
...  
Keyword(s):  
Short Stature ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Catalytic Subunit ◽  
Facial Dysmorphism ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Single Base Pair Substitution ◽  
Single Base Pair ◽  
Phase Progression

DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

scholarly journals The Meiosis-Specific Crs1 Cyclin Is Required for Efficient S-Phase Progression and Stable Nuclear Architecture

2021 ◽  
Vol 22 (11) ◽  
pp. 5483
Author(s):  
Luisa F. Bustamante-Jaramillo ◽  
Celia Ramos ◽  
Cristina Martín-Castellanos
Keyword(s):  
Cell Cycle ◽  
Translational Control ◽  
Cell Cycle Progression ◽  
Nuclear Architecture ◽  
Strand Break ◽  
Spindle Pole ◽  
S Phase ◽  
Cycle Progression ◽  
Single Wave ◽  
Phase Progression

Cyclins and CDKs (Cyclin Dependent Kinases) are key players in the biology of eukaryotic cells, representing hubs for the orchestration of physiological conditions with cell cycle progression. Furthermore, as in the case of meiosis, cyclins and CDKs have acquired novel functions unrelated to this primal role in driving the division cycle. Meiosis is a specialized developmental program that ensures proper propagation of the genetic information to the next generation by the production of gametes with accurate chromosome content, and meiosis-specific cyclins are widespread in evolution. We have explored the diversification of CDK functions studying the meiosis-specific Crs1 cyclin in fission yeast. In addition to the reported role in DSB (Double Strand Break) formation, this cyclin is required for meiotic S-phase progression, a canonical role, and to maintain the architecture of the meiotic chromosomes. Crs1 localizes at the SPB (Spindle Pole Body) and is required to stabilize the cluster of telomeres at this location (bouquet configuration), as well as for normal SPB motion. In addition, Crs1 exhibits CDK(Cdc2)-dependent kinase activity in a biphasic manner during meiosis, in contrast to a single wave of protein expression, suggesting a post-translational control of its activity. Thus, Crs1 displays multiple functions, acting both in cell cycle progression and in several key meiosis-specific events.

scholarly journals p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Longtao Wu ◽  
Clayton D. Crawley ◽  
Andrea Garofalo ◽  
Jackie W. Nichols ◽  
Paige-Ashley Campbell ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Human Cancer ◽  
S Phase ◽  
Post Translational Modification ◽  
Chromosomal Breakage ◽  
Cycle Progression ◽  
Genome Wide ◽  
Phase Progression

Abstract p50, the mature product of NFKB1, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.

scholarly journals Mi-2/NuRD complex function is required for normal S phase progression and assembly of pericentric heterochromatin

2011 ◽  
Vol 22 (17) ◽  
pp. 3094-3102 ◽  
Author(s):  
Jennifer K. Sims ◽  
Paul A. Wade
Keyword(s):  
Cell Cycle Progression ◽  
Complex Function ◽  
Pericentric Heterochromatin ◽  
S Phase ◽  
Nurd Complex ◽  
Cycle Progression ◽  
Atpase Subunit ◽  
Chromatin Remodeling Complex ◽  
Damage Response ◽  
Phase Progression

During chromosome duplication, it is essential to replicate not only the DNA sequence, but also the complex nucleoprotein structures of chromatin. Pericentric heterochromatin is critical for silencing repetitive elements and plays an essential structural role during mitosis. However, relatively little is understood about its assembly and maintenance during replication. The Mi2/NuRD chromatin remodeling complex tightly associates with actively replicating pericentric heterochromatin, suggesting a role in its assembly. Here we demonstrate that depletion of the catalytic ATPase subunit CHD4/Mi-2β in cells with a dampened DNA damage response results in a slow-growth phenotype characterized by delayed progression through S phase. Furthermore, we observe defects in pericentric heterochromatin maintenance and assembly. Our data suggest that chromatin assembly defects are sensed by an ATM-dependent intra–S phase chromatin quality checkpoint, resulting in a temporal block to the transition from early to late S phase. These findings implicate Mi-2β in the maintenance of chromatin structure and proper cell cycle progression.

scholarly journals A novel translation inhibitor, mersicarpine, inhibits S-phase progression and induces apoptosis in HL60 cells

2021 ◽  
Vol 85 (1) ◽  
pp. 92-96
Author(s):  
Tomoko Shiobara ◽  
Yoko Nagumo ◽  
Rie Nakajima ◽  
Tohru Fukuyama ◽  
Satoshi Yokoshima ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Leukemia Cell ◽  
Structural Features ◽  
S Phase ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Cycle Progression ◽  
Human Leukemia Cell Line ◽  
Phase Progression ◽  
Translation Inhibitor

Abstract Mersicarpine is an aspidosperma alkaloid isolated from the Kopsia genus of plants. Its intriguing structural features have attracted much attention in synthetic organic chemistry, but no biological activity has been reported. Here, we report the effects of mersicarpine on human leukemia cell line HL60. At concentrations above 30 µm, mersicarpine reversibly arrested cell cycle progression in S-phase. At higher concentrations, it induced not only production of reactive oxygen species, but also apoptosis. Macromolecular synthesis assay revealed that mersicarpine specifically inhibits protein synthesis. These results suggest that mersicarpine is a novel translation inhibitor that induces apoptosis.

scholarly journals The Stress-activated Protein Kinase Hog1 Mediates S Phase Delay in Response to Osmostress

2009 ◽  
Vol 20 (15) ◽  
pp. 3572-3582 ◽  
Author(s):  
Gilad Yaakov ◽  
Alba Duch ◽  
María García-Rubio ◽  
Josep Clotet ◽  
Javier Jimenez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Replication Complex ◽  
Extracellular Stimuli ◽  
Phase Progression ◽  
Cell Cycle Machinery

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to osmostress activates the Hog1 SAPK, which modulates cell cycle progression at G1 and G2 by the phosphorylation of elements of the cell cycle machinery, such as Sic1 and Hsl1, and by down-regulation of G1 and G2 cyclins. Here, we show that upon stress, Hog1 also modulates S phase progression. The control of S phase is independent of the S phase DNA damage checkpoint and of the previously characterized Hog1 cell cycle targets Sic1 and Hsl1. Hog1 uses at least two distinct mechanisms in its control over S phase progression. At early S phase, the SAPK prevents firing of replication origins by delaying the accumulation of the S phase cyclins Clb5 and Clb6. In addition, Hog1 prevents S phase progression when activated later in S phase or cells containing a genetic bypass for cyclin-dependent kinase activity. Hog1 interacts with components of the replication complex and delays phosphorylation of the Dpb2 subunit of the DNA polymerase. The two mechanisms of Hog1 action lead to delayed firing of origins and prolonged replication, respectively. The Hog1-dependent delay of replication could be important to allow Hog1 to induce gene expression before replication.

scholarly journals SAMHD1 Phosphorylation at T592 Regulates Cellular Localization and S-phase Progression

2021 ◽  
Vol 8 ◽  
Author(s):  
Stephanie Batalis ◽  
LeAnn C. Rogers ◽  
Wayne O. Hemphill ◽  
Christopher H. Mauney ◽  
David A. Ornelles ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Localization ◽  
Cellular Localization ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Oxygen Species ◽  
Wild Type ◽  
Cycle Progression ◽  
Catalytically Active ◽  
Phase Progression

SAMHD1 activity is regulated by a network of mechanisms including phosphorylation, oxidation, oligomerization, and others. Significant questions remain about the effects of phosphorylation on SAMHD1 function and activity. We investigated the effects of a SAMHD1 T592E phosphorylation mimic on its cellular localization, catalytic activity, and cell cycle progression. We found that the SAMHD1 T592E is a catalytically active enzyme that is inhibited by protein oxidation. SAMHD1 T592E is retained in the nucleus at higher levels than the wild-type protein during growth factor-mediated signaling. This nuclear localization protects SAMHD1 from oxidation by cytoplasmic reactive oxygen species. The SAMHD1 T592E phosphomimetic further inhibits the cell cycle S/G2 transition. This has significant implications for SAMHD1 function in regulating innate immunity, antiviral response and DNA replication.

scholarly journals Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression

2012 ◽  
Vol 198 (5) ◽  
pp. 793-798 ◽  
Author(s):  
David G. Crider ◽  
Luis J. García-Rodríguez ◽  
Pallavi Srivastava ◽  
Leonardo Peraza-Reyes ◽  
Krishna Upadhyaya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mitochondrial Dna ◽  
Cell Cycle Progression ◽  
Dna Helicase ◽  
S Phase ◽  
Noncoding Dna ◽  
Cycle Progression ◽  
Checkpoint Pathway ◽  
Oxidase Inhibition ◽  
Phase Progression

The Chk2-mediated deoxyribonucleic acid (DNA) damage checkpoint pathway is important for mitochondrial DNA (mtDNA) maintenance. We show in this paper that mtDNA itself affects cell cycle progression. Saccharomyces cerevisiae rho0 cells, which lack mtDNA, were defective in G1- to S-phase progression. Deletion of subunit Va of cytochrome c oxidase, inhibition of F1F0 adenosine triphosphatase, or replacement of all mtDNA-encoded genes with noncoding DNA did not affect G1- to S-phase progression. Thus, the cell cycle progression defect in rho0 cells is caused by loss of DNA within mitochondria and not loss of respiratory activity or mtDNA-encoded genes. Rad53p, the yeast Chk2 homologue, was required for inhibition of G1- to S-phase progression in rho0 cells. Pif1p, a DNA helicase and Rad53p target, underwent Rad53p-dependent phosphorylation in rho0 cells. Thus, loss of mtDNA activated an established checkpoint kinase that inhibited G1- to S-phase progression. These findings support the existence of a Rad53p-regulated checkpoint that regulates G1- to S-phase progression in response to loss of mtDNA.

scholarly journals Defective Gene Expression, S Phase Progression, and Maturation during Hematopoiesis in E2F1/E2F2 Mutant Mice

2003 ◽  
Vol 23 (10) ◽  
pp. 3607-3622 ◽  
Author(s):  
Feng X. Li ◽  
Jing W. Zhu ◽  
Christopher J. Hogan ◽  
James DeGregori
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
S Phase ◽  
Mutant Mice ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Cycle Progression ◽  
Phase Progression

ABSTRACT E2F plays critical roles in cell cycle progression by regulating the expression of genes involved in nucleotide synthesis, DNA replication, and cell cycle control. We show that the combined loss of E2F1 and E2F2 in mice leads to profound cell-autonomous defects in the hematopoietic development of multiple cell lineages. E2F2 mutant mice show erythroid maturation defects that are comparable with those observed in patients with megaloblastic anemia. Importantly, hematopoietic defects observed in E2F1/E2F2 double-knockout (DKO) mice appear to result from impeded S phase progression in hematopoietic progenitor cells. During DKO B-cell maturation, differentiation beyond the large pre-BII-cell stage is defective, presumably due to failed cell cycle exit, and the cells undergo apoptosis. However, apoptosis appears to be the consequence of failed maturation, not the cause. Despite the accumulation of hematopoietic progenitor cells in S phase, the combined loss of E2F1 and E2F2 results in significantly decreased expression and activities of several E2F target genes including cyclin A2. Our results indicate specific roles for E2F1 and E2F2 in the induction of E2F target genes, which contribute to efficient expansion and maturation of hematopoietic progenitor cells. Thus, E2F1 and E2F2 play essential and redundant roles in the proper coordination of cell cycle progression with differentiation which is necessary for efficient hematopoiesis.

scholarly journals Histone Deacetylase 3 Regulates Cyclin A Stability

2013 ◽  
Vol 288 (29) ◽  
pp. 21096-21104 ◽  
Author(s):  
Miriam Vidal-Laliena ◽  
Edurne Gallastegui ◽  
Francesca Mateo ◽  
Marian Martínez-Balbás ◽  
Maria Jesús Pujol ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Cell Cycle Progression ◽  
Proteasome Inhibitors ◽  
Cyclin A ◽  
S Phase ◽  
Cycle Progression ◽  
Histone Deacetylase 3 ◽  
Lysine Residues ◽  
Phase Progression

PCAF and GCN5 acetylate cyclin A at specific lysine residues targeting it for degradation at mitosis. We report here that histone deacetylase 3 (HDAC3) directly interacts with and deacetylates cyclin A. HDAC3 interacts with a domain included in the first 171 aa of cyclin A, a region involved in the regulation of its stability. In cells, overexpression of HDAC3 reduced cyclin A acetylation whereas the knocking down of HDAC3 increased its acetylation. Moreover, reduction of HDAC3 levels induced a decrease of cyclin A that can be reversed by proteasome inhibitors. These results indicate that HDAC3 is able to regulate cyclin A degradation during mitosis via proteasome. Interestingly, HDAC3 is abruptly degraded at mitosis also via proteasome thus facilitating cyclin A acetylation by PCAF/GCN5, which will target cyclin A for degradation. Because cyclin A is crucial for S phase progression and mitosis entry, the knock down of HDAC3 affects cell cycle progression specifically at both, S phase and G2/M transition. In summary we propose here that HDAC3 regulates cyclin A stability by counteracting the action of the acetylases PCAF/GCN5.

scholarly journals p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2

2005 ◽  
Vol 168 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Geneviève Rodier ◽  
Constantin Makris ◽  
Philippe Coulombe ◽  
Anthony Scime ◽  
Keiko Nakayama ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Inhibitory Effect ◽  
S Phase ◽  
Cycle Progression ◽  
Pocket Proteins ◽  
Phase Progression ◽  
F Box Protein ◽  
Serum Dependent ◽  
Phase Entry

Cell cycle progression is negatively regulated by the pocket proteins pRb, p107, and p130. However, the mechanisms responsible for this inhibition are not fully understood. Here, we show that overexpression of p107 in fibroblasts inhibits Cdk2 activation and delays S phase entry. The inhibition of Cdk2 activity is correlated with the accumulation of p27, consequent to a decreased degradation of the protein, with no change of Thr187 phosphorylation. Instead, we observed a marked decrease in the abundance of the F-box receptor Skp2 in p107-overexpressing cells. Reciprocally, Skp2 accumulates to higher levels in p107−/− embryonic fibroblasts. Ectopic expression of Skp2 restores p27 down-regulation and DNA synthesis to the levels observed in parental cells, whereas inactivation of Skp2 abrogates the inhibitory effect of p107 on S phase entry. We further show that the serum-dependent increase in Skp2 half-life observed during G1 progression is impaired in cells overexpressing p107. We propose that p107, in addition to its interaction with E2F, inhibits cell proliferation through the control of Skp2 expression and the resulting stabilization of p27.

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