Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since interferon inducible 2',5'-oligoadenylate (2,5An) synthetase activity is present in a wide variety of cells and is affected by various hormonal conditions, primary human mammary tumor extracts were examined for the constitutive presence of this enzyme and its possible relationship with the various hormonal receptor levels in these tissues. Further, since 2,5An synthetase has been implicated as a possible factor controlling cell replication, we assayed DNA polymerases in these same tumor extracts to determine any correlation between 2,5An synthetase activity and growth potential. A survey of the soluble extracts from 24 different surgically removed human mammary tumor specimens for 2,5An synthetase activity indicated that this enzyme was indeed present in all extracts but in widely varying amounts of activity (31-2,666 nmol adenosine 5'-phosphate incorporated/mg protein). The 2,5An synthesized in the enzymic reactions ranged in size from di- to hexamers, with trimers being the abundant 2,5An in the majority of tumors. A comparison of the assay results for estrogen and progestin receptors with 2,5An synthesis indicated that high 2,5An synthetase activity was found in both estrogen or progestin positive and negative tumors. Thus, 2,5An synthetase activity was unrelated (r = 0.329 and 0.077, respectively, for estrogen and progestin receptors) to the hormonal receptor content of these tumors. A similar comparison was made between 2,5An synthesis and assay results for the activities of DNA polymerase alpha, regarded as the principal DNA replicating enzyme, and DNA polymerase beta, regarded as the DNA repair enzyme. Although the activity of the polymerases were also quite varied, the majority of tumor extracts demonstrated higher alpha polymerase activity with no parallel difference between the alpha and beta enzymes. There was, however, a weak correlation (r = 0.751) between 2,5An synthetase activity and DNA polymerase alpha activity among the tumors examined. Less of a correlation existed with DNA polymerase beta activity (r = 0.600). These results suggested that the potential of the tumors to synthesize 2,5An was unrelated to their hormonal responsiveness and only weakly related to their growth potential reflected by DNA polymerase alpha activity.
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PMID:2',5'-oligoadenylate synthetase activity in human mammary tumors and its potential correlation with tumor growth or hormonal responsiveness. 377 41

DNA repair takes place in the context of chromatin. Previous studies showed that histones impair base excision repair (BER) of modified bases at both the excision and synthesis steps. We examined BER of uracil in a glucocorticoid response element (GRE) complexed with the glucocorticoid receptor DNA binding domain (GR-DBD). Five substrates were designed, each containing a unique C-->U substitution within the mouse mammary tumor virus promoter, one located within each GRE half-site and the others located outside the GRE. To examine distinct steps of BER, DNA cleavage by uracil-DNA glycosylase and Ape1 endonuclease was used to assess initiation, dCTP incorporation by DNA polymerase (pol) beta was used to measure repair synthesis, and DNA ligase I was used to seal the nick. For uracil sites within the GRE, there was a reduced rate of uracil-DNA glycosylase/Ape1 activity following GR-DBD binding. Cleavage in the right half-site, with higher GR-DBD binding affinity, was reduced approximately 5-fold, whereas cleavage in the left half-site was reduced approximately 3.8-fold. Conversely, uracil-directed cleavage outside the GRE was unaffected by GR-DBD binding. Surprisingly, there was no reduction in the rate of pol beta synthesis or DNA ligase activity on any of the fragments bound to GR-DBD. Indeed, we observed a small increase ( approximately 1.5-2.2-fold) in the rate of pol beta synthesis at uracil residues in both the GRE and one site six nucleotides downstream. These results highlight the potential for both positive and negative impacts of DNA-transcription factor binding on the rate of BER.
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PMID:Base excision repair in a glucocorticoid response element: effect of glucocorticoid receptor binding. 2062 60