title: Flipping of alkylated DNA damage bridges base and nucleotide excision repair.
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.affiliation: Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Tubbs
authors.forename: Vitaly
authors.initials: V
authors.lastname: Latypov
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Kanugula
authors.forename: Amna
authors.initials: A
authors.lastname: Butt
authors.forename: Manana
authors.initials: M
authors.lastname: Melikishvili
authors.forename: Rolf
authors.initials: R
authors.lastname: Kraehenbuehl
authors.forename: Oliver
authors.initials: O
authors.lastname: Fleck
authors.forename: Andrew
authors.initials: A
authors.lastname: Marriott
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Barbara
authors.initials: B
authors.lastname: Verbeek
authors.forename: Gail
authors.initials: G
authors.lastname: McGown
authors.forename: Mary
authors.initials: M
authors.lastname: Thorncroft
authors.forename: Mauro F
authors.initials: MF
authors.lastname: Santibanez-Koref
authors.forename: Christopher
authors.initials: C
authors.lastname: Millington
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Arvai
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Kroeger
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Peterson
authors.forename: David M
authors.initials: DM
authors.lastname: Williams
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fried
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pegg
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000737:chemistry* / Q000378:metabolism*; D000478:Alkylation; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: C473029:O(6)-(4-oxo-4-(3-pyridyl)butyl)guanine; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; C510506:ATL1 protein, S pombe; D019883:Alkyl and Aryl Transferases