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Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Lookup NU author(s): Dr Mauro Santibanez Koref

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Abstract

Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O-6-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 O-6-methylguanine or cigarette-smoke-derived O-6-4-(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.


Publication metadata

Author(s): Tubbs JL, Latypov V, Kanugula S, Butt A, Melikishvili M, Kraehenbuehl R, Fleck O, Marriott A, Watson AJ, Verbeek B, McGown G, Thorncroft M, Santibanez-Koref MF, Millington C, Arvai AS, Kroeger MD, Peterson LA, Williams DM, Fried MG, Margison GP, Pegg AE, Tainer JA

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2009

Volume: 459

Issue: 7248

Pages: 808-813

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature08076

DOI: 10.1038/nature08076


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Funding

Funder referenceFunder name
CHEMORES
Skaggs Institute for Chemical Biology
Cancer Research-UK
US Department of Energy
CA018137NIH
CA59887NIH
CA097209NIH
CR675North West Cancer Research Fund
GM070662NIH

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