Flipping of alkylated DNA damage bridges base and nucleotide excision repair.
AuthorsTubbs, Julie L
Latypov, Vitaly F
Marriott, Andrew S
Watson, Amanda J
Thorncroft, Mary R
Santibanez-Koref, Mauro F
Arvai, Andrew S
Kroeger, Matthew D
Peterson, Lisa A
Williams, David M
Margison, Geoffrey P
Pegg, Anthony E
Tainer, John A
AffiliationSkaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
MetadataShow full item record
AbstractAlkyltransferase-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.
CitationFlipping of alkylated DNA damage bridges base and nucleotide excision repair. 2009, 459 (7248):808-13 Nature
- Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein.
- Authors: Aramini JM, Tubbs JL, Kanugula S, Rossi P, Ertekin A, Maglaqui M, Hamilton K, Ciccosanti CT, Jiang M, Xiao R, Soong TT, Rost B, Acton TB, Everett JK, Pegg AE, Tainer JA, Montelione GT
- Issue date: 2010 Apr 30
- Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.
- Authors: Wilkinson OJ, Latypov V, Tubbs JL, Millington CL, Morita R, Blackburn H, Marriott A, McGown G, Thorncroft M, Watson AJ, Connolly BA, Grasby JA, Masui R, Hunter CA, Tainer JA, Margison GP, Williams DM
- Issue date: 2012 Nov 13
- DNA binding and nucleotide flipping by the human DNA repair protein AGT.
- Authors: Daniels DS, Woo TT, Luu KX, Noll DM, Clarke ND, Pegg AE, Tainer JA
- Issue date: 2004 Aug
- Conserved structural motifs governing the stoichiometric repair of alkylated DNA by O(6)-alkylguanine-DNA alkyltransferase.
- Authors: Daniels DS, Tainer JA
- Issue date: 2000 Aug 30
- Role of alkyltransferase-like (ATL) protein in repair of methylated DNA lesions in Thermus thermophilus.
- Authors: Onodera T, Morino K, Tokishita S, Morita R, Masui R, Kuramitsu S, Ohta T
- Issue date: 2011 Mar