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Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II.
Proc Natl Acad Sci U S A. 2004 May 11; 101(19):7275-80.PN

Abstract

Malondialdehyde, a genotoxic byproduct of lipid peroxidation, reacts with guanine in DNA to form pyrimido[1,2-alpha]purin-10(3H)one (M(1)dG), the first endogenous DNA lesion found to be a target of nucleotide excision repair enzymes. A subpathway of nucleotide excision repair, transcription-coupled repair, is thought to occur when RNA polymerase (RNAP) is arrested at damage in transcribed DNA strands and might function for efficient removal of M(1)dG in active genes. Results presented here show that M(1)dG and its stable, exocyclic analog 1,N(2)-propanodeoxyguanine (PdG), arrest translocation of T7 RNAP and mammalian RNAPII when located in the transcribed strand of a DNA template. M(1)dG paired with thymine is exocyclic and poses a stronger block to transcription than the acyclic N(2)-(3-oxo-1-propenyl)-dG, formed upon cytosine-catalyzed opening of M(1)dG in duplex DNA. PdG is a complete block to RNAPII regardless of base pairing. The elongation factor TFIIS (SII) induces reversal and RNA transcript cleavage by RNAPII arrested at PdG. Thus, arrested RNAPII complexes may be stable at M(1)dG in cells and may resume transcription once the offending adduct is removed. The conclusion from this work is that malondialdehyde adducts in the transcribed strand of expressed genes are strong blocks to RNAPs and are targets for cellular transcription-coupled repair. If so, then M(1)dG, already known to be highly mutagenic in human cells, also may contribute to apoptosis in the developing tissues of individuals with Cockayne's syndrome, a hereditary disorder characterized by transcription-coupled repair deficiency.

Authors+Show Affiliations

Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15123825

Citation

Cline, Susan D., et al. "Malondialdehyde Adducts in DNA Arrest Transcription By T7 RNA Polymerase and Mammalian RNA Polymerase II." Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 19, 2004, pp. 7275-80.
Cline SD, Riggins JN, Tornaletti S, et al. Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II. Proc Natl Acad Sci USA. 2004;101(19):7275-80.
Cline, S. D., Riggins, J. N., Tornaletti, S., Marnett, L. J., & Hanawalt, P. C. (2004). Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II. Proceedings of the National Academy of Sciences of the United States of America, 101(19), 7275-80.
Cline SD, et al. Malondialdehyde Adducts in DNA Arrest Transcription By T7 RNA Polymerase and Mammalian RNA Polymerase II. Proc Natl Acad Sci USA. 2004 May 11;101(19):7275-80. PubMed PMID: 15123825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II. AU - Cline,Susan D, AU - Riggins,James N, AU - Tornaletti,Silvia, AU - Marnett,Lawrence J, AU - Hanawalt,Philip C, Y1 - 2004/04/27/ PY - 2004/5/5/pubmed PY - 2004/7/9/medline PY - 2004/5/5/entrez SP - 7275 EP - 80 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 101 IS - 19 N2 - Malondialdehyde, a genotoxic byproduct of lipid peroxidation, reacts with guanine in DNA to form pyrimido[1,2-alpha]purin-10(3H)one (M(1)dG), the first endogenous DNA lesion found to be a target of nucleotide excision repair enzymes. A subpathway of nucleotide excision repair, transcription-coupled repair, is thought to occur when RNA polymerase (RNAP) is arrested at damage in transcribed DNA strands and might function for efficient removal of M(1)dG in active genes. Results presented here show that M(1)dG and its stable, exocyclic analog 1,N(2)-propanodeoxyguanine (PdG), arrest translocation of T7 RNAP and mammalian RNAPII when located in the transcribed strand of a DNA template. M(1)dG paired with thymine is exocyclic and poses a stronger block to transcription than the acyclic N(2)-(3-oxo-1-propenyl)-dG, formed upon cytosine-catalyzed opening of M(1)dG in duplex DNA. PdG is a complete block to RNAPII regardless of base pairing. The elongation factor TFIIS (SII) induces reversal and RNA transcript cleavage by RNAPII arrested at PdG. Thus, arrested RNAPII complexes may be stable at M(1)dG in cells and may resume transcription once the offending adduct is removed. The conclusion from this work is that malondialdehyde adducts in the transcribed strand of expressed genes are strong blocks to RNAPs and are targets for cellular transcription-coupled repair. If so, then M(1)dG, already known to be highly mutagenic in human cells, also may contribute to apoptosis in the developing tissues of individuals with Cockayne's syndrome, a hereditary disorder characterized by transcription-coupled repair deficiency. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/15123825/Malondialdehyde_adducts_in_DNA_arrest_transcription_by_T7_RNA_polymerase_and_mammalian_RNA_polymerase_II_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15123825 DB - PRIME DP - Unbound Medicine ER -