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Preventing replication fork collapse to maintain genome integrity.
Cortez D
(2015) DNA Repair (Amst) 32: 149-157
MeSH Terms: Animals, DNA, DNA Damage, DNA Polymerase III, DNA Repair, DNA Replication, Gene Expression Regulation, Genomic Instability, Humans, Mice, Proliferating Cell Nuclear Antigen, Saccharomyces cerevisiae, Xenopus laevis
Show Abstract · Added February 4, 2016
Billions of base pairs of DNA must be replicated trillions of times in a human lifetime. Complete and accurate replication once and only once per cell division cycle is essential to maintain genome integrity and prevent disease. Impediments to replication fork progression including difficult to replicate DNA sequences, conflicts with transcription, and DNA damage further add to the genome maintenance challenge. These obstacles frequently cause fork stalling, but only rarely cause a failure to complete replication. Robust mechanisms ensure that stalled forks remain stable and capable of either resuming DNA synthesis or being rescued by converging forks. However, when failures do happen the fork collapses leading to genome rearrangements, cell death and disease. Despite intense interest, the mechanisms to repair damaged replication forks, stabilize them, and ensure successful replication remain only partly understood. Different models of fork collapse have been proposed with varying descriptions of what happens to the DNA and replisome. Here, I will define fork collapse and describe what is known about how the replication checkpoint prevents it to maintain genome stability.
Copyright © 2015 Elsevier B.V. All rights reserved.
0 Communities
1 Members
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13 MeSH Terms
Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins.
Guilliam TA, Jozwiakowski SK, Ehlinger A, Barnes RP, Rudd SG, Bailey LJ, Skehel JM, Eckert KA, Chazin WJ, Doherty AJ
(2015) Nucleic Acids Res 43: 1056-68
MeSH Terms: DNA Primase, DNA Primers, DNA Replication, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Humans, Mitochondrial Proteins, Multifunctional Enzymes, Mutagenesis, Proliferating Cell Nuclear Antigen, Protein Interaction Domains and Motifs, Replication Protein A
Show Abstract · Added January 20, 2015
PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed in both re-priming and translesion synthesis mechanisms to bypass nuclear and mitochondrial DNA lesions. In this report, we investigate how the enzymatic activities of human PrimPol are regulated. We show that, unlike other TLS polymerases, PrimPol is not stimulated by PCNA and does not interact with it in vivo. We identify that PrimPol interacts with both of the major single-strand binding proteins, RPA and mtSSB in vivo. Using NMR spectroscopy, we characterize the domains responsible for the PrimPol-RPA interaction, revealing that PrimPol binds directly to the N-terminal domain of RPA70. In contrast to the established role of SSBs in stimulating replicative polymerases, we find that SSBs significantly limit the primase and polymerase activities of PrimPol. To identify the requirement for this regulation, we employed two forward mutation assays to characterize PrimPol's replication fidelity. We find that PrimPol is a mutagenic polymerase, with a unique error specificity that is highly biased towards insertion-deletion errors. Given the error-prone disposition of PrimPol, we propose a mechanism whereby SSBs greatly restrict the contribution of this enzyme to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
1 Communities
3 Members
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12 MeSH Terms
BID binds to replication protein A and stimulates ATR function following replicative stress.
Liu Y, Vaithiyalingam S, Shi Q, Chazin WJ, Zinkel SS
(2011) Mol Cell Biol 31: 4298-309
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BH3 Interacting Domain Death Agonist Protein, Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Replication, DNA-Binding Proteins, Humans, Models, Biological, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Interaction Domains and Motifs, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Recombinant Proteins, Replication Protein A, Signal Transduction, Stress, Physiological
Show Abstract · Added December 5, 2013
Proapoptotic BH3-interacting death domain agonist (BID) regulates apoptosis and the DNA damage response. Following replicative stress, BID associates with proteins of the DNA damage sensor complex, including replication protein A (RPA), ataxia telangiectasia and Rad3 related (ATR), and ATR-interacting protein (ATRIP), and facilitates an efficient DNA damage response. We have found that BID stimulates the association of RPA with components of the DNA damage sensor complex through interaction with the basic cleft of the N-terminal domain of the RPA70 subunit. Disruption of the BID-RPA interaction impairs the association of ATR-ATRIP with chromatin as well as ATR function, as measured by CHK1 activation and recovery of DNA replication following hydroxyurea (HU). We further demonstrate that the association of BID with RPA stimulates the association of ATR-ATRIP to the DNA damage sensor complex. We propose a model in which BID associates with RPA and stimulates the recruitment and/or stabilization of ATR-ATRIP to the DNA damage sensor complex.
2 Communities
2 Members
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27 MeSH Terms
Angiotensin II: breathtaking in the renal medulla.
Haase VH
(2011) Kidney Int 79: 269-71
MeSH Terms: Actins, Angiotensin II, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Transdifferentiation, Collagen Type I, Collagen Type III, Fibrosis, Humans, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Medulla, Procollagen-Proline Dioxygenase, Proliferating Cell Nuclear Antigen, Rats, Tissue Inhibitor of Metalloproteinase-1, Up-Regulation, Vimentin
Show Abstract · Added August 19, 2013
Angiotensin II (Ang II) is a major contributor to the progression of renal fibrosis. Wang and colleagues provide evidence that signaling through the prolyl-4-hydroxylase domain (PHD)-hypoxia-inducible factor-1 (HIF-1) pathway mediates profibrotic effects of Ang II in rat renal medullary interstitial cells under normoxic conditions, thus placing the HIF oxygen-sensing pathway into the center of an Ang II-induced profibrotic signaling cascade.
0 Communities
1 Members
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18 MeSH Terms
Translesion synthesis across abasic lesions by human B-family and Y-family DNA polymerases α, δ, η, ι, κ, and REV1.
Choi JY, Lim S, Kim EJ, Jo A, Guengerich FP
(2010) J Mol Biol 404: 34-44
MeSH Terms: DNA, DNA Damage, DNA Polymerase I, DNA Polymerase III, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Humans, Kinetics, Nuclear Proteins, Nucleotidyltransferases, Oligonucleotides, Proliferating Cell Nuclear Antigen
Show Abstract · Added March 26, 2014
Abasic (apurinic/apyrimidinic, AP) sites are the most common DNA lesions formed in cells, induce severe blocks to DNA replication, and are highly mutagenic. Human Y-family translesion DNA polymerases (pols) such as pols η, ι, κ, and REV1 have been suggested to play roles in replicative bypass across many DNA lesions where B-family replicative pols stall, but their individual catalytic functions in AP site bypass are not well understood. In this study, oligonucleotides containing a synthetic abasic lesion (tetrahydrofuran analogue) were compared for catalytic efficiency and base selectivity with human Y-family pols η, ι, κ, and REV1 and B-family pols α and δ. Pol η and pol δ/proliferating cell nuclear antigen (PCNA) copied past AP sites quite effectively and generated products ranging from one-base to full-length extension. Pol ι and REV1 readily incorporated one base opposite AP sites but then stopped. Pols κ and α were severely blocked at AP sites. Pol η preferentially inserted T and A; pol ι inserted T, G, and A; pol κ inserted C and A; REV1 preferentially inserted C opposite AP sites. The B-family pols α and δ/PCNA preferentially inserted A (85% and 58%, respectively) consonant with the A-rule hypothesis. Pols η and δ/PCNA were much more efficient in next-base extension, preferably from A positioned opposite an AP site, than pol κ. These results suggest that AP sites might be bypassed with moderate efficiency by single B- and Y-family pols or combinations, possibly by REV1 and pols ι, η, and δ/PCNA at the insertion step opposite the lesion and by pols η and δ/PCNA at the subsequent extension step. The patterns of the base preferences of human B-family and Y-family pols in both insertion and extension are pertinent to some of the mutagenesis events induced by AP lesions in human cells.
Copyright © 2010 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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13 MeSH Terms
Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells.
Das G, Choi Y, Sicinski P, Levine EM
(2009) Neural Dev 4: 15
MeSH Terms: Animals, Animals, Newborn, Bromodeoxyuridine, Cell Cycle, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p27, Embryo, Mammalian, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Mice, Mice, Knockout, Neurogenesis, Neurons, Otx Transcription Factors, Proliferating Cell Nuclear Antigen, Retina, Thymidine, Transcription Factor Brn-3B, Tubulin
Show Abstract · Added November 2, 2015
BACKGROUND - Maintaining the correct balance of proliferation versus differentiation in retinal progenitor cells (RPCs) is essential for proper development of the retina. The cell cycle regulator cyclin D1 is expressed in RPCs, and mice with a targeted null allele at the cyclin D1 locus (Ccnd1-/-) have microphthalmia and hypocellular retinas, the latter phenotype attributed to reduced RPC proliferation and increased photoreceptor cell death during the postnatal period. How cyclin D1 influences RPC behavior, especially during the embryonic period, is unclear.
RESULTS - In this study, we show that embryonic RPCs lacking cyclin D1 progress through the cell cycle at a slower rate and exit the cell cycle at a faster rate. Consistent with enhanced cell cycle exit, the relative proportions of cell types born in the embryonic period, such as retinal ganglion cells and photoreceptor cells, are increased. Unexpectedly, cyclin D1 deficiency decreases the proportions of other early born retinal neurons, namely horizontal cells and specific amacrine cell types. We also found that the laminar positioning of horizontal cells and other cell types is altered in the absence of cyclin D1. Genetically replacing cyclin D1 with cyclin D2 is not efficient at correcting the phenotypes due to the cyclin D1 deficiency, which suggests the D-cyclins are not fully redundant. Replacement with cyclin E or inactivation of cyclin-dependent kinase inhibitor p27Kip1 restores the balance of RPCs and retinal cell types to more normal distributions, which suggests that regulation of the retinoblastoma pathway is an important function for cyclin D1 during embryonic retinal development.
CONCLUSION - Our findings show that cyclin D1 has important roles in RPC cell cycle regulation and retinal histogenesis. The reduction in the RPC population due to a longer cell cycle time and to an enhanced rate of cell cycle exit are likely to be the primary factors driving retinal hypocellularity and altered output of precursor populations in the embryonic Ccnd1-/- retina.
0 Communities
1 Members
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21 MeSH Terms
Structural basis for DNA binding by replication initiator Mcm10.
Warren EM, Vaithiyalingam S, Haworth J, Greer B, Bielinsky AK, Chazin WJ, Eichman BF
(2008) Structure 16: 1892-901
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Biophysical Phenomena, DNA, DNA Mutational Analysis, DNA Polymerase I, DNA Replication, DNA-Binding Proteins, Minichromosome Maintenance Proteins, Models, Biological, Models, Molecular, Molecular Sequence Data, Mutation, Nuclear Magnetic Resonance, Biomolecular, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Zinc Fingers
Show Abstract · Added March 11, 2014
Mcm10 is an essential eukaryotic DNA replication protein required for assembly and progression of the replication fork. The highly conserved internal domain (Mcm10-ID) has been shown to physically interact with single-stranded (ss) DNA, DNA polymerase alpha, and proliferating cell nuclear antigen (PCNA). The crystal structure of Xenopus laevis Mcm10-ID presented here reveals a DNA binding architecture composed of an oligonucleotide/oligosaccharide-fold followed in tandem by a variant and highly basic zinc finger. NMR chemical shift perturbation and mutational studies of DNA binding activity in vitro reveal how Mcm10 uses this unique surface to engage ssDNA. Corresponding mutations in Saccharomyces cerevisiae result in increased sensitivity to replication stress, demonstrating the functional importance of DNA binding by this region of Mcm10 to replication. In addition, mapping Mcm10 mutations known to disrupt PCNA, polymerase alpha, and DNA interactions onto the crystal structure provides insight into how Mcm10 might coordinate protein and DNA binding within the replisome.
1 Communities
2 Members
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23 MeSH Terms
NFAT4 deficiency results in incomplete liver regeneration following partial hepatectomy.
Pierre KB, Jones CM, Pierce JM, Nicoud IB, Earl TM, Chari RS
(2009) J Surg Res 154: 226-33
MeSH Terms: Animals, Apoptosis, Bone Morphogenetic Protein 4, Cell Division, Fibroblast Growth Factors, Hepatectomy, JNK Mitogen-Activated Protein Kinases, Liver, Liver Regeneration, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, NFATC Transcription Factors, Proliferating Cell Nuclear Antigen, Proto-Oncogene Proteins c-fos, Signal Transduction, Up-Regulation
Show Abstract · Added January 10, 2014
BACKGROUND - Liver regeneration following partial hepatectomy requires the orchestration of highly regulated molecular pathways; a change in the abundance or activity of a specific gene product has the potential to adversely affect this process. The nuclear factor of activated T-cells (NFAT) transcription factors represent a family of gene transcription signaling intermediates that translate receptor-dependent signaling events into specific transcriptional responses using the Ras/Raf pathway.
MATERIALS AND METHODS - Eight-week old NFAT4 knockout (KO) mice and their wild type counterparts (Balb-c) underwent two-thirds partial hepatectomy. The animals were sacrificed and their livers were harvested at specific time points during regeneration. Recovery of liver mass was measured for each time point. PCR analysis was used to analyze expression levels of the immediate early genes c-fos, c-jun and c-myc as well as downstream effectors of NFAT4 including FGF-18 and BMP-4.
RESULTS - Hepatocyte proliferation and thus liver regeneration following hepatectomy was suppressed in NFAT4 knockout (KO) mice. Statistical significance was reached at 1 h, 7 d, and 10 d (P < 0.05) with a 22% median reduction in regeneration of liver mass in the NFAT4 KO mice by 10 d, at which time liver regeneration should be complete in mice. The immediate early gene c-fos was elevated in NFAT4 KO mice during early regeneration with a median value at 1 h and 1 d of 1.60E-08 and 1.09E-08 versus 6.10E-09 and 1.55E-09 in the Balb-c mice. C-jun, in contrast, was elevated during late regeneration in the NFAT4 KO mice (3.40E-09 and 5.67E-09 at 7 and 10 d, respectively) in comparison with the Balb-c mice (7.76E-10 and 1.24E-09, respectively.). NFAT2 was also up-regulated in the NFAT4 KO mice; however, no changes were detected in its downstream effectors, CCR1 and CCL3.
CONCLUSIONS - We demonstrated that NFAT4 deficiency impairs hepatic regeneration in a murine model proving that NFAT4 plays an important yet unclear role in liver regeneration; its absence may be compensated by c-fos, c-jun, and NFAT2 expression changes.
0 Communities
1 Members
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18 MeSH Terms
Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina.
Barton KM, Levine EM
(2008) Dev Dyn 237: 672-82
MeSH Terms: Animals, Cell Cycle, Cell Cycle Proteins, Cyclin A, Cyclin A2, Cyclin B, Cyclin B1, Cyclin D, Cyclins, Histones, Mice, Minichromosome Maintenance Complex Component 6, Phosphorylation, Proliferating Cell Nuclear Antigen, Retina
Show Abstract · Added November 2, 2015
A challenge in studying organogenesis is the ability to identify progenitor cell populations. To address this problem, we characterized the expression patterns of cell cycle proteins during mouse retinal development and used flow cytometry to determine the expression profiles in the cell cycle. We found that MCM6 and PCNA are expressed in essentially all retinal progenitor cells throughout the proliferative period and these proteins are readily detectable in all cell cycle phases. Furthermore, their expression levels are downregulated as cells exit the cell cycle and differentiate. We also analyzed the expression of Cyclins D1, A2, and B1, and phosphorylated Histone H3 and found unexpected expression patterns and cell cycle profiles. The combined utilization of the markers tested and the use of flow cytometry should further facilitate the study of stem and progenitor cell behavior during development and in adult tissues.
(c) 2008 Wiley-Liss, Inc.
0 Communities
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15 MeSH Terms
Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis.
Yang HC, Ma LJ, Ma J, Fogo AB
(2006) Kidney Int 69: 1756-64
MeSH Terms: Angiopoietin-like 4 Protein, Angiopoietins, Animals, Antibiotics, Antineoplastic, Blood Pressure, Blood Proteins, Body Weight, Drug Evaluation, Preclinical, Glomerular Filtration Rate, Hypoglycemic Agents, Kidney, Male, PPAR gamma, Pioglitazone, Plasminogen Activator Inhibitor 1, Podocytes, Proliferating Cell Nuclear Antigen, Protective Agents, Puromycin Aminonucleoside, RNA, Messenger, Rats, Rats, Sprague-Dawley, Sclerosis, Thiazolidinediones, Vascular Endothelial Growth Factor A
Show Abstract · Added January 20, 2012
We have previously observed increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in podocytes in both rat and human sclerotic conditions. The aim of the present study was to investigate whether activation of PPARgamma can attenuate podocyte injury-associated glomerulosclerosis in vivo. Puromycin aminonucleoside nephropathy was induced in Sprague-Dawley rats. The animals then either received no further treatment (control group (CONT)); or the PPARgamma agonist, pioglitazone (Pio) starting at week 0 (P0); or Pio starting at week 6 (P6), with sacrifice at week 12. At week 12, urinary protein excretion and systolic blood pressure were similar in the three groups. Glomerular filtration rate and glomerulosclerosis were decreased in CONT and P0 at week 12, but preserved in P6 rats. PPARgamma expression in CONT at 12 weeks was increased in podocytes and in mesangial WT-1 cells in segmentally sclerotic glomeruli, with less Wilms' tumor 1 (WT-1) staining. In P6 rats, mesangial WT-1 staining was lessened, but podocyte staining was strongly accentuated. Delayed treatment with Pio partially restored podocyte staining and tended to decrease the ratio of proliferating cell nuclear antigen-positive to apoptotic cells in glomeruli. Both treatment groups showed significantly reduced infiltrating glomerular macrophages and plasminogen activator inhibitor-1 mRNA expression in cortex, with no change in transforming growth factor-beta1 and tissue inhibitor of metalloproteinase-1 mRNA. Pio also decreased renal cortical angiopoietin-like protein 4 expression to almost 20% of CONT group, associated with increased vascular endothelial-derived growth factor expression in glomeruli. We conclude that treatment with PPARgamma agonist has protective effects on progression of glomerulosclerosis.
1 Communities
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25 MeSH Terms