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Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, Seoane JA, Farshidfar F, Bowlby R, Islam M, Kim J, Chatila W, Akbani R, Kanchi RS, Rabkin CS, Willis JE, Wang KK, McCall SJ, Mishra L, Ojesina AI, Bullman S, Pedamallu CS, Lazar AJ, Sakai R, Cancer Genome Atlas Research Network, Thorsson V, Bass AJ, Laird PW
(2018) Cancer Cell 33: 721-735.e8
MeSH Terms: Adenocarcinoma, Aneuploidy, Chromosomal Instability, DNA Methylation, DNA Polymerase II, DNA-Binding Proteins, Epigenesis, Genetic, Female, Gastrointestinal Neoplasms, Gene Regulatory Networks, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Male, Microsatellite Instability, MutL Protein Homolog 1, Mutation, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), RNA-Binding Proteins, SOX9 Transcription Factor
Show Abstract · Added October 30, 2019
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
Copyright © 2018 Elsevier Inc. All rights reserved.
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21 MeSH Terms
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.
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13 MeSH Terms
Replication, repair, and translesion polymerase bypass of N⁶-oxopropenyl-2'-deoxyadenosine.
Maddukuri L, Shuck SC, Eoff RL, Zhao L, Rizzo CJ, Guengerich FP, Marnett LJ
(2013) Biochemistry 52: 8766-76
MeSH Terms: DNA Polymerase I, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Deoxyadenosines, Humans, Kinetics, Mutagenicity Tests, Mutagens, Sulfolobus solfataricus
Show Abstract · Added March 7, 2014
The oxidative stress products malondialdehyde and base propenal react with DNA bases forming the adduction products 3-(2'-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-a]purin-10(3H)-one (M1dG) and N(6)-(oxypropenyl)-2'-deoxyadenosine (OPdA). M1dG is mutagenic in vivo and miscodes in vitro, but little work has been done on OPdA. To improve our understanding of the effect of OPdA on polymerase activity and mutagenicity, we evaluated the ability of the translesion DNA polymerases hPols η, κ, and ι to bypass OPdA in vitro. hPols η and κ inserted dNTPs opposite the lesion and extended the OPdA-modified primer to the terminus. hPol ι inserted dNTPs opposite OPdA but failed to fully extend the primer. Steady-state kinetic analysis indicated that these polymerases preferentially insert dTTP opposite OPdA, although less efficiently than opposite dA. Minimal incorrect base insertion was observed for all polymerases, and dCTP was the primary mis-insertion event. Examining replicative and repair polymerases revealed little effect of OPdA on the Sulfolobus solfataricus polymerase Dpo1 or the Klenow fragment of Escherichia coli DNA polymerase I. Bacteriophage T7 DNA polymerase displayed a reduced level of OPdA bypass compared to unmodified DNA, and OPdA nearly completely blocked the activity of base excision repair polymerase hPol β. This work demonstrates that bypass of OPdA is generally error-free, modestly decreases the catalytic activity of most polymerases, and blocks hPol β polymerase activity. Although mis-insertion opposite OPdA is relatively weak, the efficiency of bypass may introduce A → G transitions observed in vivo.
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10 MeSH Terms
Sequence context modulation of polycyclic aromatic hydrocarbon-induced mutagenesis.
Chary P, Stone MP, Lloyd RS
(2013) Environ Mol Mutagen 54: 652-8
MeSH Terms: Base Pair Mismatch, DNA Adducts, DNA Polymerase I, DNA-Directed DNA Polymerase, Escherichia coli, Molecular Structure, Mutagenesis, Mutagens, Polycyclic Aromatic Hydrocarbons, Stereoisomerism
Show Abstract · Added March 7, 2014
DNA structural perturbations that are induced by site specifically and stereospecifically defined benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) adducts are directly correlated with mutagenesis, leading to cellular transformation. Although previous investigations had established that replication of DNAs containing N(6) -BPDE dA adducts at the second position in the N-ras codon 61(CAA) (61(2) ) resulted exclusively in A to G transitions, NMR analyses not only established the structural basis for this transition mutation but also predicted that if the adduct were positioned at the third position in the same codon, an expanded spectra of mutations was possible. To test this prediction, replication of DNAs containing C10 S-BPDE and C10 R-BPDE lesions linked through the N(6) position of adenine in the sequence context N-ras codon 61, position 3 (C10 S-BPDE and C10 R-BPDE at 61(3) ) was carried out in Escherichia coli, and these data revealed a wide mutation spectrum. In addition to A to G transitions produced by replication of both lesions, replication of the C10 S-BPDE and C10 R-BPDE adducts also yielded A to C and A to T transversions, respectively. Analyses of single nucleotide incorporation using Sequenase 2.0 and exonuclease-deficient E. coli Klenow fragment and pol II not only revealed high fidelity synthesis but also demonstrated the same hierarchy of preference opposite a particular lesion, independent of the sequence context. Primer extension assays with the two lesions at N-ras 61(3) resulted in truncated products, with the C10 S-BPDE adducts being more blocking than C10 R-BPDE lesions, and termination of synthesis was more pronounced at position 61(3) than at 61(2) for each of the lesions.
Copyright © 2013 Wiley Periodicals, Inc.
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10 MeSH Terms
Down-regulation of replication factor C-40 (RFC40) causes chromosomal missegregation in neonatal and hypertrophic adult rat cardiac myocytes.
Ata H, Shrestha D, Oka M, Ochi R, Jong CJ, Gebb S, Benjamin J, Schaffer S, Hobart HH, Downey J, McMurtry I, Gupte R
(2012) PLoS One 7: e39009
MeSH Terms: Animals, Animals, Newborn, Cardiomegaly, Cells, Cultured, Chromosomes, DNA Polymerase III, Down-Regulation, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Myocardium, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Replication Protein C
Show Abstract · Added March 30, 2020
BACKGROUND - Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) and DNA polymerase δ (Pol δ) proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied.
METHODS - We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol δ message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control) and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH) for rat chromosome 12.
RESULTS - RFC40-mRNA and protein was undetectable, whereas Pol δ message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol δ message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re-expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers.
CONCLUSION - Our novel findings suggest that transcription of RFC40 is suppressed in the normal adult cardiac myocytes and its insufficient re-expression may be responsible for causing chromosomal missegregation/aneuploidy and in cardiac myocytes during right ventricular hypertrophy.
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MeSH Terms
Roles of the four DNA polymerases of the crenarchaeon Sulfolobus solfataricus and accessory proteins in DNA replication.
Choi JY, Eoff RL, Pence MG, Wang J, Martin MV, Kim EJ, Folkmann LM, Guengerich FP
(2011) J Biol Chem 286: 31180-93
MeSH Terms: Bacterial Proteins, DNA, DNA Damage, DNA Polymerase I, DNA Polymerase II, DNA Polymerase III, DNA Polymerase beta, DNA Replication, DNA-Directed DNA Polymerase, Sulfolobus solfataricus
Show Abstract · Added March 7, 2014
The hyperthermophilic crenarchaeon Sulfolobus solfataricus P2 encodes three B-family DNA polymerase genes, B1 (Dpo1), B2 (Dpo2), and B3 (Dpo3), and one Y-family DNA polymerase gene, Dpo4, which are related to eukaryotic counterparts. Both mRNAs and proteins of all four DNA polymerases were constitutively expressed in all growth phases. Dpo2 and Dpo3 possessed very low DNA polymerase and 3' to 5' exonuclease activities in vitro. Steady-state kinetic efficiencies (k(cat)/K(m)) for correct nucleotide insertion by Dpo2 and Dpo3 were several orders of magnitude less than Dpo1 and Dpo4. Both the accessory proteins proliferating cell nuclear antigen and the clamp loader replication factor C facilitated DNA synthesis with Dpo3, as with Dpo1 and Dpo4, but very weakly with Dpo2. DNA synthesis by Dpo2 and Dpo3 was remarkably decreased by single-stranded binding protein, in contrast to Dpo1 and Dpo4. DNA synthesis in the presence of proliferating cell nuclear antigen, replication factor C, and single-stranded binding protein was most processive with Dpo1, whereas DNA lesion bypass was most effective with Dpo4. Both Dpo2 and Dpo3, but not Dpo1, bypassed hypoxanthine and 8-oxoguanine. Dpo2 and Dpo3 bypassed uracil and cis-syn cyclobutane thymine dimer, respectively. High concentrations of Dpo2 or Dpo3 did not attenuate DNA synthesis by Dpo1 or Dpo4. We conclude that Dpo2 and Dpo3 are much less functional and more thermolabile than Dpo1 and Dpo4 in vitro but have bypass activities across hypoxanthine, 8-oxoguanine, and either uracil or cis-syn cyclobutane thymine dimer, suggesting their catalytically limited roles in translesion DNA synthesis past deaminated, oxidized base lesions and/or UV-induced damage.
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10 MeSH Terms
1,N2-Etheno-2'-deoxyguanosine adopts the syn conformation about the glycosyl bond when mismatched with deoxyadenosine.
Shanmugam G, Kozekov ID, Guengerich FP, Rizzo CJ, Stone MP
(2011) Chem Res Toxicol 24: 1071-9
MeSH Terms: Base Pair Mismatch, DNA Polymerase I, DNA Polymerase II, DNA Polymerase beta, Deoxyadenosines, Escherichia coli, Hydrogen Bonding, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Oligodeoxyribonucleotides, Protons, Sulfolobus solfataricus, Transition Temperature
Show Abstract · Added March 7, 2014
The oligodeoxynucleotide 5'-CGCATXGAATCC-3'·5'-GGATTCAATGCG-3' containing 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-εdG) opposite deoxyadenosine (named the 1,N(2)-εdG·dA duplex) models the mismatched adenine product associated with error-prone bypass of 1,N(2)-εdG by the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) and by Escherichia coli polymerases pol I exo(-) and pol II exo(-). At pH 5.2, the T(m) of this duplex was increased by 3 °C as compared to the duplex in which the 1,N(2)-εdG lesion is opposite dC, and it was increased by 2 °C compared to the duplex in which guanine is opposite dA (the dG·dA duplex). A strong NOE between the 1,N(2)-εdG imidazole proton and the anomeric proton of the attached deoxyribose, accompanied by strong NOEs to the minor groove A(20) H2 proton and the mismatched A(19) H2 proton from the complementary strand, establish that 1,N(2)-εdG rotated about the glycosyl bond from the anti to the syn conformation. The etheno moiety was placed into the major groove. This resulted in NOEs between the etheno protons and T(5) CH(3). A strong NOE between A(20) H2 and A(19) H2 protons established that A(19), opposite to 1,N(2)-εdG, adopted the anti conformation and was directed toward the helix. The downfield shifts of the A(19) amino protons suggested protonation of dA. Thus, the protonated 1,N(2)-εdG·dA base pair was stabilized by hydrogen bonds between 1,N(2)-εdG N1 and A(19) N1H(+) and between 1,N(2)-εdG O(9) and A(19)N(6)H. The broad imino proton resonances for the 5'- and 3'-flanking bases suggested that both neighboring base pairs were perturbed. The increased stability of the 1,N(2)-εdG·dA base pair, compared to that of the 1,N(2)-εdG·dC base pair, correlated with the mismatch adenine product observed during the bypass of 1,N(2)-εdG by the Dpo4 polymerase, suggesting that stabilization of this mismatch may be significant with regard to the biological processing of 1,N(2)-εdG.
© 2011 American Chemical Society
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13 MeSH Terms
DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase.
Paeschke K, Capra JA, Zakian VA
(2011) Cell 145: 678-91
MeSH Terms: DNA Copy Number Variations, DNA Helicases, DNA Polymerase II, DNA Replication, G-Quadruplexes, S Phase, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added April 18, 2017
G-quadruplex (G4) DNA structures are extremely stable four-stranded secondary structures held together by noncanonical G-G base pairs. Genome-wide chromatin immunoprecipitation was used to determine the in vivo binding sites of the multifunctional Saccharomyces cerevisiae Pif1 DNA helicase, a potent unwinder of G4 structures in vitro. G4 motifs were a significant subset of the high-confidence Pif1-binding sites. Replication slowed in the vicinity of these motifs, and they were prone to breakage in Pif1-deficient cells, whereas non-G4 Pif1-binding sites did not show this behavior. Introducing many copies of G4 motifs caused slow growth in replication-stressed Pif1-deficient cells, which was relieved by spontaneous mutations that eliminated their ability to form G4 structures, bind Pif1, slow DNA replication, and stimulate DNA breakage. These data suggest that G4 structures form in vivo and that they are resolved by Pif1 to prevent replication fork stalling and DNA breakage.
Copyright © 2011 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Structural basis for proficient incorporation of dTTP opposite O6-methylguanine by human DNA polymerase iota.
Pence MG, Choi JY, Egli M, Guengerich FP
(2010) J Biol Chem 285: 40666-72
MeSH Terms: Bacterial Proteins, Base Pairing, Catalytic Domain, DNA, DNA Polymerase I, DNA Polymerase beta, DNA-Directed DNA Polymerase, Deoxycytosine Nucleotides, Geobacillus stearothermophilus, Guanine, Humans, Hydrogen Bonding, Kinetics, Structure-Activity Relationship, Sulfolobus, Thymine Nucleotides
Show Abstract · Added March 7, 2014
O(6)-methylguanine (O(6)-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S-adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase ι core enzyme was determined for nucleoside triphosphate incorporation opposite O(6)-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol ι, which showed that dTTP incorporation occurs with high efficiency opposite O(6)-methylG. Misincorporation of dTTP opposite O(6)-methylG occurred with ∼6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol ι with O(6)-methylG as the template base and incoming dCTP or dTTP were solved and showed that O(6)-methylG is rotated into the syn conformation in the pol ι active site and that dTTP misincorporation by pol ι is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O(6)-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O(6)-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O(6) atoms of O(6)-methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O(6)-methylG by human pol ι, in contrast to the mispairing modes observed previously for O(6)-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I.
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16 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.
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13 MeSH Terms