Biomedical subjects

A Grollman

Publications and source records attributed to A Grollman.

At least 19 recordsLinked to original sources

PubMed2001

Translesion DNA synthesis catalyzed by human pol eta and pol kappa across 1,N6-ethenodeoxyadenosine.

1,N(6)-Ethenodeoxyadenosine, a DNA adduct generated by exogenous and endogenous sources, severely blocks DNA synthesis and induces miscoding events in human cells. To probe the mechanism for in vivo translesion DNA synthesis across this adduct, in vitro primer extension studies were conducted using newly identified human DNA polymerases (pol) eta and kappa, which have been shown to catalyze translesion DNA synthesis past several DNA lesions. Steady-state kinetic analyses and analysis of translesion products have revealed that the synthesis is >100-fold more efficient with pol eta than with pol kappa and that both error-free and error-prone syntheses are observed with these enzymes. The miscoding events include both base substitution and frameshift mutations. These results suggest that both polymerases, particularly pol eta, may contribute to the translesion DNA synthesis events observed for 1,N(6)-ethenodeoxyadenosine in human cells.

Animals↗

PubMed2000

Responses to the major acrolein-derived deoxyguanosine adduct in Escherichia coli.

Acrolein, a reactive alpha,beta-unsaturated aldehyde found ubiquitously in the environment and formed endogenously in mammalian cells, reacts with DNA to form an exocyclic DNA adduct, 3H-8-hydroxy-3-(beta-D-2'-deoxyribofuranosyl)-5,6,7,8-tetrahydropyrido[3,2-a]purine-9-one (gamma-OH-PdG). The cellular processing and mutagenic potential of gamma-OH-PdG have been examined, using a site-specific approach in which a single adduct is embedded in double-strand plasmid DNA. Analysis of progeny plasmid reveals that this adduct is excised by nucleotide excision repair. The apparent level of inhibition of DNA synthesis is approximately 70% in Escherichia coli DeltarecA, uvrA. The block to DNA synthesis can be overcome partially by recA-dependent recombination repair. Targeted G --> T transversions were observed at a frequency of 7 x 10(-4)/translesion synthesis. Inactivation of polB, dinB, and umuD,C genes coding for "SOS" DNA polymerases did not affect significantly the efficiency or fidelity of translesion synthesis. In vitro primer extension experiments revealed that the Klenow fragment of polymerase I catalyzes error-prone synthesis, preferentially incorporating dAMP and dGMP opposite gamma-OH-PdG. We conclude from this study that DNA polymerase III catalyzes translesion synthesis across gamma-OH-PdG in an error-free manner. Nucleotide excision repair, recombination repair, and highly accurate translesion synthesis combine to protect E. coli from the potential genotoxicity of this DNA adduct.

Acrolein↗

PubMed1989

NMR studies of exocyclic 1,N2-propanodeoxyguanosine adducts (X) opposite purines in DNA duplexes: protonated X(syn).A(anti) pairing (acidic pH) and X(syn).G(anti) pairing (neutral pH) at the lesion site.

Proton and phosphorus two-dimensional NMR studies are reported for the complementary d(C1-A2-T3-G4-X5-G6-T7-A8-C9).d(G10-T11-A12-C13-A14-C15-A 16-T17-G18) nonanucleotide duplex (designated X.A 9-mer) that contains a 1,N2-propanodeoxyguanosine exocyclic adduct, X5, opposite deoxyadenosine A14 in the center of the helix. The NMR studies detect a pH-dependent conformational transition; this paper focuses on the structure present at pH 5.8. The two-dimensional NOESY studies of the X.A 9-mer duplex in H2O and D2O solution establish that X5 adopts a syn orientation while A14 adopts an anti orientation about the glycosidic bond at the lesion site. The large downfield shift of the amino protons of A14 demonstrates protonation of the deoxyadenosine base at pH 5.8 such that the protonated X5(syn).A14(anti) pair is stabilized by two hydrogen bonds at low pH. At pH 5.8, the observed NOE between the H8 proton of X5 and the H2 proton of A14 in the X.A 9-mer duplex demonstrates unequivocally the formation of the protonated X5(syn).A14(anti) pair. The 1,N2-propano bridge of X5(syn) is located in the major groove. Selective NOEs from the exocyclic methylene protons of X5 to the major groove H8 proton of flanking G4 but not G6 of the G4-X5-G6 segment provide additional structural constraints on the local conformation at the lesion site. A perturbation in the phosphodiester backbone is detected at the C13-A14 phosphorus located at the lesion site by 31P NMR spectroscopy. The two-dimensional NMR studies have been extended to the related complementary X.G 9-mer duplex that contains a central X5.G14 lesion in a sequence that is otherwise identical with the X.A 9-mer duplex. The NMR experimental parameters are consistent with formation of a pH-independent X5(syn).G14(anti) pair stabilized by two hydrogen bonds with the 1,N2-propano exocyclic adduct of X5(syn) located in the major groove.

Base Composition↗

PubMed1980

Hypertension: a critical survey.

Explore the source record for details and available documents.

Arteriosclerosis↗

PubMed1978

A conjecture about the prevalence of essential hypertension and its high incidence in the black.

The high incidence in certain racial groups of essential hypertension is attributed to the advantage which this disease confers when the availability of sodium is deficient in the environment. This conjecture is supported by alterations in behaviour of sodium in the body economy of the hypertensive as evidenced by: the effects of sodium depletion on the blood pressure; the elevated sodium content of the tissues in the hypertensive; the reduced rate of sodium excretion in spontaneous and experimental hypertensive disease; the fact that hypertension can be induced in the offspring of rats subjected to a deficient sodium intake or to natriuretic drugs during pregnancy; the increased appetite for sodium observed in the hypertensive; and the effect of an increased sodium intake on the blood pressure. It is suggested that the substantial within-species variation in the incidence of essential hypertension reflects the availability of the sodium requirement of the individual suffering from the genetic mutation responsible for this disease.

Africa, Central↗

PubMed1976

The mechanism of contraction of rat aorta to various agonists.

To elucidate the mechanism of contraction of the smooth muscle of the rat's aorta, its response to norepinephrine (NE), 5-hydroxytrypatamine (5-HT) and potassium chloride (KCI) was determined before and after pretreatment with reserpine and beta-diethylamionethyl 2-2-diphenylpropyl acetate (SKF 525-A). Unlike the rabbit's aorta, contraction of the rat's aorta induced by NE was inhibited by SKF 525-A. After the induction of maximal contraction, SKF 525-A induced a graded rapid relaxation after KCl, less so after 5-HT, and least after NE. Pretreatment with reserpine failed to induce supersensitivity to NE. After incubation in a Ca++-free or Na+ and Ca++-free Krebs solution, the rat's aorta failed to contract even on the addition of Ca++ or NE.

Animals↗

PubMed1974