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Flipping of alkylated DNA damage bridges base and nucleotide excision repair.

Tubbs, Julie L
; 
Latypov, Vitaly F
; 
Kanugula, Sreenivas
; 
Butt, Amna
; 
Melikishvili, Manana
; 
Kraehenbuehl, Rolf
; 
Fleck, Oliver
; 
Marriott, Andrew S
; 
Watson, Amanda J
; 
Verbeek, Barbara
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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.
Authors
Tubbs, Julie L
Latypov, Vitaly F
Kanugula, Sreenivas
Butt, Amna
Melikishvili, Manana
Kraehenbuehl, Rolf
Fleck, Oliver
Marriott, Andrew S
Watson, Amanda J
Verbeek, Barbara
McGown, Gail
Thorncroft, Mary R
Santibanez-Koref, Mauro F
Millington, Christopher
Arvai, Andrew S
Kroeger, Matthew D
Peterson, Lisa A
Williams, David M
Fried, Mike
Margison, Geoffrey P
Pegg, Anthony E
Tainer, John A
Affiliation
Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Description
Date
2009-06-11
Publisher
Collections
All Paterson Institute for Cancer Research
Carcinogenesis Group
Medical Oncology
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Keywords
Type
Article
Citation
Flipping of alkylated DNA damage bridges base and nucleotide excision repair. 2009, 459 (7248):808-13 Nature
Journal Title
Journal ISSN
Volume Title
URI
http://hdl.handle.net/10541/85244
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