IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v459y2009i7248d10.1038_nature08076.html
   My bibliography  Save this article

Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Author

Listed:
  • Julie L. Tubbs

    (The Scripps Research Institute, La Jolla, California 92037, USA)

  • Vitaly Latypov

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Sreenivas Kanugula

    (Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA)

  • Amna Butt

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Manana Melikishvili

    (Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA)

  • Rolf Kraehenbuehl

    (NWCRF Institute, Bangor University
    Present addresses: Cancer Research UK DNA Damage Response Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK (R.K.); Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark (O.F.); Department of Toxicology, University of Mainz, D-55131 Mainz, Germany (B.V.).)

  • Oliver Fleck

    (NWCRF Institute, Bangor University
    Present addresses: Cancer Research UK DNA Damage Response Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK (R.K.); Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark (O.F.); Department of Toxicology, University of Mainz, D-55131 Mainz, Germany (B.V.).)

  • Andrew Marriott

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Amanda J. Watson

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Barbara Verbeek

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
    Present addresses: Cancer Research UK DNA Damage Response Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK (R.K.); Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark (O.F.); Department of Toxicology, University of Mainz, D-55131 Mainz, Germany (B.V.).)

  • Gail McGown

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Mary Thorncroft

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Mauro F. Santibanez-Koref

    (Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK)

  • Christopher Millington

    (Centre for Chemical Biology, University of Sheffield)

  • Andrew S. Arvai

    (The Scripps Research Institute, La Jolla, California 92037, USA)

  • Matthew D. Kroeger

    (The Scripps Research Institute, La Jolla, California 92037, USA)

  • Lisa A. Peterson

    (University of Minnesota, Minneapolis, Minnesota 55455, USA)

  • David M. Williams

    (Centre for Chemical Biology, University of Sheffield)

  • Michael G. Fried

    (Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA)

  • Geoffrey P. Margison

    (Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK)

  • Anthony E. Pegg

    (Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA)

  • John A. Tainer

    (The Scripps Research Institute, La Jolla, California 92037, USA
    Bioenergy and Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA)

Abstract

Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O6-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O6-methylguanine or cigarette-smoke-derived O6-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.

Suggested Citation

  • Julie L. Tubbs & Vitaly Latypov & Sreenivas Kanugula & Amna Butt & Manana Melikishvili & Rolf Kraehenbuehl & Oliver Fleck & Andrew Marriott & Amanda J. Watson & Barbara Verbeek & Gail McGown & Mary Th, 2009. "Flipping of alkylated DNA damage bridges base and nucleotide excision repair," Nature, Nature, vol. 459(7248), pages 808-813, June.
    • Handle: RePEc:nat:nature:v:459:y:2009:i:7248:d:10.1038_nature08076
    DOI: 10.1038/nature08076
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature08076
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature08076?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:459:y:2009:i:7248:d:10.1038_nature08076. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.