The Nonbulky DNA Lesions Spiroiminodihydantoin and 5-Guanidinohydantoin Significantly Block Human RNA Polymerase II Elongation in Vitro

Biochemistry
Marina KolbanovskiyVladimir Shafirovich

Abstract

The most common, oxidatively generated lesion in cellular DNA is 8-oxo-7,8-dihydroguanine, which can be oxidized further to yield highly mutagenic spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) in DNA. In human cell-free extracts, both lesions can be excised by base excision repair and global genomic nucleotide excision repair. However, it is not known if these lesions can be removed by transcription-coupled DNA repair (TCR), a pathway that clears lesions from DNA that impede RNA synthesis. To determine if Sp or Gh impedes transcription, which could make each a viable substrate for TCR, either an Sp or a Gh lesion was positioned on the transcribed strand of DNA under the control of a promoter that supports transcription by human RNA polymerase II. These constructs were incubated in HeLa nuclear extracts that contained active RNA polymerase II, and the resulting transcripts were resolved by denaturing polyacrylamide gel electrophoresis. The structurally rigid Sp strongly blocks transcription elongation, permitting 1.6 ± 0.5% nominal lesion bypass. In contrast, the conformationally flexible Gh poses less of a block to human RNAPII, allowing 9 ± 2% bypass. Furthermore, fractional lesion bypass for Sp and Gh is minimally ...Continue Reading

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Citations

Jan 19, 2019·International Journal of Molecular Sciences·Bayan Bokhari, Sudha Sharma
Apr 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Juntaek OhDong Wang
Jul 18, 2019·DNA Repair·Harini Sampath, R Stephen Lloyd
Mar 24, 2021·Progress in Biophysics and Molecular Biology·Altaf H SarkerTapas K Hazra
Jul 19, 2021·Seminars in Cancer Biology·Andrew VonHandorfAlvaro Puga

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