Tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can specifically target bacterial DNA ligases and can distinguish them from human DNA ligase I

2015 ◽  
Vol 13 (19) ◽  
pp. 5475-5487 ◽  
Author(s):  
Nisha Yadav ◽  
Taran Khanam ◽  
Ankita Shukla ◽  
Niyati Rai ◽  
Kanchan Hajela ◽  
...  
Keyword(s):  
Dna Ligase ◽  
Indole Derivatives ◽  
Dna Metabolism ◽  
Bacterial Dna ◽  
Dna Ligases ◽  
Human Dna ◽  
Dna Ligase I ◽  
Critical Components

DNA ligases are critical components for DNA metabolism in all organisms.

Identification of a novel human DNA ligase I inhibitor that promotes cellular apoptosis in DLD-1 cells: an in silico and in vitro mechanistic study

RSC Advances ◽  
2016 ◽  
Vol 6 (97) ◽  
pp. 94574-94587 ◽  
Author(s):  
Deependra Kumar Singh ◽  
Mohd. Kamil Hussain ◽  
Shagun Krishna ◽  
Amit Laxmikant Deshmukh ◽  
Mohammad Shameem ◽  
...  
Keyword(s):  
In Silico ◽  
Specific Inhibitor ◽  
Mechanistic Study ◽  
Dna Ligase ◽  
Dna Ligases ◽  
Human Dna ◽  
Dna Ligase I ◽  
Cellular Apoptosis

The compound S-097/98 is a specific inhibitor of hLig1. As shown in the figure, the compound inhibits only hLig1 while other human and non-human DNA ligases are not inhibited.

scholarly journals Mammalian DNA ligase III: molecular cloning, chromosomal localization, and expression in spermatocytes undergoing meiotic recombination.

1995 ◽  
Vol 15 (10) ◽  
pp. 5412-5422 ◽  
Author(s):  
J Chen ◽  
A E Tomkinson ◽  
W Ramos ◽  
Z B Mackey ◽  
S Danehower ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Chromosome 17 ◽  
Dna Ligase ◽  
Cdna Clones ◽  
Dna Ligases ◽  
Cell Extracts ◽  
Human Dna ◽  
Dna Ligase I ◽  
Dna Ligase Iii

Three biochemically distinct DNA ligase activities have been identified in mammalian cell extracts. We have recently purified DNA ligase II and DNA ligase III to near homogeneity from bovine liver and testis tissue, respectively. Amino acid sequencing studies indicated that these enzymes are encoded by the same gene. In the present study, human and murine cDNA clones encoding DNA ligase III were isolated with probes based on the peptide sequences. The human DNA ligase III cDNA encodes a polypeptide of 862 amino acids, whose sequence is more closely related to those of the DNA ligases encoded by poxviruses than to replicative DNA ligases, such as human DNA ligase I. In vitro transcription and translation of the cDNA produced a catalytically active DNA ligase similar in size and substrate specificity to the purified bovine enzyme. The DNA ligase III gene was localized to human chromosome 17, which eliminated this gene as a candidate for the cancer-prone disease Bloom syndrome that is associated with DNA joining abnormalities. DNA ligase III is ubiquitously expressed at low levels, except in the testes, in which the steady-state levels of DNA ligase III mRNA are at least 10-fold higher than those detected in other tissues and cells. Since DNA ligase I mRNA is also present at high levels in the testes, we examined the expression of the DNA ligase genes during spermatogenesis. DNA ligase I mRNA expression correlated with the contribution of proliferating spermatogonia cells to the testes, in agreement with the previously defined role of this enzyme in DNA replication. In contrast, elevated levels of DNA ligase III mRNA were observed in primary spermatocytes undergoing recombination prior to the first meiotic division. Therefore, we suggest that DNA ligase III seals DNA strand breaks that arise during the process of meiotic recombination in germ cells and as a consequence of DNA damage in somatic cells.

scholarly journals Thermodynamics of Human DNA Ligase I Trimerization and Association with DNA Polymerase β

1998 ◽  
Vol 273 (32) ◽  
pp. 20540-20550 ◽  
Author(s):  
Emilios K. Dimitriadis ◽  
Rajendra Prasad ◽  
Mary K. Vaske ◽  
Ling Chen ◽  
Alan E. Tomkinson ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Ligase ◽  
Dna Polymerase Β ◽  
Human Dna ◽  
Dna Ligase I

MAMMALIAN DNA LIGASES; ALTERED DNA LIGASE I IN BLOOM'S SYNDROME

1991 ◽  
pp. 71
Author(s):  
ALAN E. TOMKINSON ◽  
DEBORAH E. BARNES ◽  
KEN-ICHI KODAMA ◽  
EEMA ROBERTS ◽  
GRAHAM DALY ◽  
...  
Keyword(s):  
Dna Ligase ◽  
Bloom's Syndrome ◽  
Dna Ligases ◽  
Bloom’S Syndrome ◽  
Dna Ligase I

scholarly journals The ligation of pol β mismatch insertion products governs the formation of promutagenic base excision DNA repair intermediates

2020 ◽  
Vol 48 (7) ◽  
pp. 3708-3721 ◽  
Author(s):  
Melike Çağlayan
Keyword(s):  
Excision Repair ◽  
Dna Ligase ◽  
Active Site Residues ◽  
Dna Ligases ◽  
Terminal Domain ◽  
Dna Ligase I ◽  
Nucleotide Insertion ◽  
Base Excision ◽  
Ligation Step

Abstract DNA ligase I and DNA ligase III/XRCC1 complex catalyze the ultimate ligation step following DNA polymerase (pol) β nucleotide insertion during base excision repair (BER). Pol β Asn279 and Arg283 are the critical active site residues for the differentiation of an incoming nucleotide and a template base and the N-terminal domain of DNA ligase I mediates its interaction with pol β. Here, we show inefficient ligation of pol β insertion products with mismatched or damaged nucleotides, with the exception of a Watson–Crick-like dGTP insertion opposite T, using BER DNA ligases in vitro. Moreover, pol β N279A and R283A mutants deter the ligation of the promutagenic repair intermediates and the presence of N-terminal domain of DNA ligase I in a coupled reaction governs the channeling of the pol β insertion products. Our results demonstrate that the BER DNA ligases are compromised by subtle changes in all 12 possible noncanonical base pairs at the 3′-end of the nicked repair intermediate. These findings contribute to understanding of how the identity of the mismatch affects the substrate channeling of the repair pathway and the mechanism underlying the coordination between pol β and DNA ligase at the final ligation step to maintain the BER efficiency.

scholarly journals Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination.

1995 ◽  
Vol 15 (6) ◽  
pp. 3206-3216 ◽  
Author(s):  
Y F Wei ◽  
P Robins ◽  
K Carter ◽  
K Caldecott ◽  
D J Pappin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cdna Clone ◽  
Dna Ligase ◽  
Dna Ligases ◽  
Dna Ligase Iv ◽  
Ligase Iv ◽  
Dna Ligase I ◽  
Cloned Cdna ◽  
Dna Ligase Iii

Three distinct DNA ligases, I to III, have been found previously in mammalian cells, but a cloned cDNA has been identified only for DNA ligase I, an essential enzyme active in DNA replication. A short peptide sequence conserved close to the C terminus of all known eukaryotic DNA ligases was used to search for additional homologous sequences in human cDNA libraries. Two different incomplete cDNA clones that showed partial homology to the conserved peptide were identified. Full-length cDNAs were obtained and expressed by in vitro transcription and translation. The 103-kDa product of one cDNA clone formed a characteristic complex with the XRCC1 DNA repair protein and was identical with the previously described DNA ligase III. DNA ligase III appears closely related to the smaller DNA ligase II. The 96-kDa in vitro translation product of the second cDNA clone was also shown to be an ATP-dependent DNA ligase. A fourth DNA ligase (DNA ligase IV) has been purified from human cells and shown to be identical to the 96-kDa DNA ligase by unique agreement between mass spectrometry data on tryptic peptides from the purified enzyme and the predicted open reading frame of the cloned cDNA. The amino acid sequences of DNA ligases III and IV share a related active-site motif and several short regions of homology with DNA ligase I, other DNA ligases, and RNA capping enzymes. DNA ligases III and IV are encoded by distinct genes located on human chromosomes 17q11.2-12 and 13q33-34, respectively.

scholarly journals Late induction of human DNA ligase I after UV-C irradiation

1995 ◽  
Vol 23 (6) ◽  
pp. 962-966 ◽  
Author(s):  
Alessandra Montecucco ◽  
Elena Savini ◽  
Giuseppe Biamonti ◽  
Miria Stefanini ◽  
Federico Focher ◽  
...  
Keyword(s):  
Dna Ligase ◽  
Human Dna ◽  
Dna Ligase I ◽  
Uv C

Human DNA ligase I completely encircles and partially unwinds nicked DNA

Nature ◽  
2004 ◽  
Vol 432 (7016) ◽  
pp. 473-478 ◽  
Author(s):  
John M. Pascal ◽  
Patrick J. O'Brien ◽  
Alan E. Tomkinson ◽  
Tom Ellenberger
Keyword(s):  
Dna Ligase ◽  
Human Dna ◽  
Dna Ligase I

scholarly journals Natural-product inhibitors of human DNA ligase I

1996 ◽  
Vol 314 (3) ◽  
pp. 993-1000 ◽  
Author(s):  
Ghee T. TAN ◽  
Sangkook LEE ◽  
Ik-Soo LEE ◽  
Jingwen CHEN ◽  
Pete LEITNER ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Natural Product ◽  
Conformational Changes ◽  
Enzyme Inhibitor ◽  
Enzymic Activity ◽  
Dna Ligase ◽  
Enzyme Active Site ◽  
Dna Relaxation ◽  
Human Dna ◽  
Dna Ligase I

Enzymic activity mediated by recombinant human DNA ligase I (hLI), in conjunction with tannin removal procedures, has been applied to a natural-product screen involving ~1000 plant extracts and various pure compounds. The primary hLI activity assay involved the measurement of the amount of radiolabelled phosphate in a synthetic nucleic acid hybrid that becomes resistant to alkaline phosphatase as a result of ligation. A bioactivity-guided fractionation scheme resulted in the isolation of ursolic [IC50 = 100 μg/ml (216 μM)] and oleanolic [IC50 = 100 μg/ml (216 μM)] acids from Tricalysia niamniamensis Hiern (Rubiaceae), which demonstrated similar DNA ligase inhibition profiles to other triterpenes such as aleuritolic acid. Protolichesterinic acid [IC50 = 6 μg/ml (20 μM)], swertifrancheside [IC50 = 8 μg/ml (11 μM)] and fulvoplumierin [IC50 = 87 μg/ml (357 μM)] represent three additional natural-product structural classes that inhibit hLI. Fagaronine chloride [IC50 = 10 μg/ml (27 μM)] and certain flavonoids are also among the pure natural products that were found to disrupt the activity of the enzyme, consistent with their nucleic acid intercalative properties. Further analyses revealed that some of the hLI-inhibitory compounds interfered with the initial adenylation step of the ligation reaction, indicating a direct interaction with the enzyme protein. However, in all cases, this enzyme–inhibitor interaction did not disrupt the DNA relaxation activity mediated by hLI. These results indicate that, although the same enzyme active site may be involved in both enzyme adenylation and DNA relaxation, inhibitors may exert allosteric effects by inducing conformational changes that disrupt only one of these activities. Studies with inhibitors are important for the assignment of specific cellular functions to these enzymes, as well as for their development into clinically useful antitumour agents.

Polymorphisms in the human DNA ligase I gene (LIG1) including a complex GT repeat

1998 ◽  
Vol 406 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Kenneth J Livak ◽  
Wayne A Little ◽  
Sylvia L Stack ◽  
Thomas A Patterson
Keyword(s):  
Dna Ligase ◽  
Human Dna ◽  
Dna Ligase I ◽  
I Gene
Sign in / Sign up

Export Citation Format

Share Document