Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Replication of DNA containing 8-oxo-7,8-dihydroguanine (8oxoG) can generate 8oxoG/A base pairs which, if uncorrected, lead to G-->T transversions. It is generally accepted that the repair of these promutagenic base pairs in human cells is initiated by the MutY DNA glycosylase homolog (hMYH). Here we provide biochemical evidence that human cell extracts perform base excision repair (BER) on both DNA strands of an 8oxoG/A mismatch. At early repair times the specificity of nucleotide incorporation indicates a preferential insertion of C opposite 8oxoG leading to the formation of 8oxoG/C pairs. This is followed by repair synthesis on the opposite DNA strand that is consistent with hOGG1-mediated correction of 8oxoG/C to G/C. Repair synthesis on either strand is completely inhibited by aphidicolin suggesting that a replicative DNA polymerase is involved in the gap filling. This is the first demonstration that repair of 8oxoG/A base pairs is by two BER events likely mediated by Poldelta/epsilon. We suggest that the Poldelta/epsilon-mediated BER is the general mode of repair when BER lesions are formed at replication forks.
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PMID:Base excision repair of adenine/8-oxoguanine mispairs by an aphidicolin-sensitive DNA polymerase in human cell extracts. 1214 42

Accumulating evidence suggests that the Rad9-Rad1-Hus1 (9-1-1) checkpoint complex, known to be a sensor of DNA damage, is also a component of DNA repair systems. Recent results show that 9-1-1 interacts with several base excision repair proteins. It binds the DNA glycosylase MutY homolog, and stimulates DNA polymerase beta, flap endonuclease 1, and DNA ligase I. 9-1-1 resembles proliferating cell nuclear antigen (PCNA), which stimulates some of these same repair enzymes, and is loaded onto DNA in a similar manner. The complex of 9-1-1 with DNA ligase I can be immunoprecipitated from human cells. Moreover, UV irradiation stimulates 9-1-1.ligase I complex formation, suggesting a role for 9-1-1 in DNA repair. Examining the nature of 9-1-1 interaction with DNA ligase I, we show that there is a similar degree of stimulation on ligation substrates with different structures, and that there is specificity for DNA ligase I. 9-1-1 improves the binding of DNA ligase I to nicked double strand DNA. Furthermore, although high concentrations of casein kinase II strongly inhibits DNA ligase I activity, it does not affect the ability of 9-1-1 to stimulate. This suggests that 9-1-1 is also an activator of DNA ligase I during DNA damage. Unlike PCNA, 9-1-1 stimulates DNA ligase I activity to the same extent on both linear and circular substrates, indicating that encirclement is not a requirement for stimulation. These data are consistent with a direct role for 9-1-1 in DNA repair, but possibly employing a different mechanism than PCNA.
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PMID:Mechanism of stimulation of human DNA ligase I by the Rad9-rad1-Hus1 checkpoint complex. 1673 26