Cheng TF, et al. (2008) Differential Blocking Effects of the Acetaldehyde-derived DNA Lesion N2-Ethyl-2'-deoxyguanosine on Transcription by Multisubunit and Single Subunit RNA Polymerases. J Biol Chem 283(41):27820-8
Abstract: Acetaldehyde (ACD), the first metabolite of ethanol, reacts with DNA to form adducts, including N2-ethyl-2'-deoxyguanosine (N2-Et-dG). While the effects of N2-Et-dG on DNA polymerases have been well studied, nothing is known about possible effects of this lesion on transcription by RNA polymerases (RNAPs). Using primer extension assays in vitro, we found that a single N2-Et-dG lesion is a strong block to both mammalian RNAPII and two other multisubunit RNAPs, (yeast RNAPII and E. coli RNAP), as well as to T7 RNAP. However, the mechanism of transcription blockage appears to differ between the multisubunit RNAPs and T7 RNAP. Specifically, all three of the multisubunit RNAPs can incorporate a single rNTP residue opposite the lesion, whereas T7 RNAP is essentially unable to do so. Using the mammalian RNAPII, we found that cytidine monophospate (CMP) is exclusively incorporated opposite the N2-Et-dG lesion. In addition, we also show that the accessory transcription factor TFIIS does not act as a lesion bypass factor, as it does for other non-bulky DNA lesions; instead, it stimulates the polymerase to remove the CMP incorporated opposite the lesion by mammalian RNAPII. We also include models of the N2-Et-dG within the active site of yeast RNAPII which are compatible with our observations.
|Status: Published||Type: Journal Article||PubMed ID: 18669632|
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