Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

John M Hinz; Yesenia Rodriguez; Michael J Smerdon

doi:10.1073/pnas.0914443107

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Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

Journal article

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Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme

John M Hinz, Yesenia Rodriguez and Michael J Smerdon

Proceedings of the National Academy of Sciences - PNAS, Vol.107(10), pp.4646-4651

03/09/2010

DOI: https://doi.org/10.1073/pnas.0914443107

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https://hdl.handle.net/2376/105809

PMCID: PMC2842065

PMID: 20176960

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Abstract

Recombinant Proteins - metabolism

Uracil-DNA Glycosidase - metabolism

Histones - chemistry

Humans

Models, Molecular

Nucleosomes - metabolism

DNA - metabolism

Rotation

DNA - chemistry

DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics

DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism

DNA Repair

Uracil - metabolism

Histones - metabolism

Nucleic Acid Conformation

Uracil-DNA Glycosidase - genetics

Uracil - chemistry

Histones play a crucial role in the organization of DNA in the nucleus, but their presence can prevent interactions with DNA binding proteins responsible for repair of DNA damage. Uracil is an abundant mutagenic lesion recognized by uracil DNA glycosylase (UDG) in the first step of base excision repair (BER). In nucleosome core particles (NCPs), we find substantial differences in UDG-directed cleavage at uracils rotationally positioned toward (U-In) or away from (U-Out) the histone core, or midway between these orientations (U-Mid). Whereas U-Out NCPs show a cleavage rate just below that of naked DNA, U-In and U-Mid NCPs have markedly slower rates of cleavage. Crosslinking of U-In DNA to histones in NCPs yields a greater reduction in cleavage rate but, surprisingly, yields a higher rate of cleavage in U-Out NCPs compared with uncrosslinked NCPs. Moreover, the next enzyme in BER, APE1, stimulates the activity of human UDG in U-Out NCPs, suggesting these enzymes interact on the surface of histones in orientations accessible to UDG. These data indicate that the activity of UDG likely requires "trapping" transiently exposed states arising from the rotational dynamics of DNA on histones.

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Title: Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme
Creators: John M Hinz - Biochemistry and Biophysics, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA
Yesenia Rodriguez
Michael J Smerdon
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.107(10), pp.4646-4651
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R37 ES002614 / NIEHS NIH HHS R01 ES002614 / NIEHS NIH HHS T32 GM008336-21 / NIGMS NIH HHS ES002614 / NIEHS NIH HHS T32 GM008336-19 / NIGMS NIH HHS R37 ES002614-31 / NIEHS NIH HHS R01 ES004106 / NIEHS NIH HHS ES004106 / NIEHS NIH HHS T32 GM008336-20 / NIGMS NIH HHS
Identifiers: 99900546820901842
Language: English
Resource Type: Journal article