title: Mechanism of replication blocking and bypass of Y-family polymerase {eta} by bulky acetylaminofluorene DNA adducts.
abstract: Heterocyclic aromatic amines produce bulky C8 guanine lesions in vivo, which interfere and disrupt DNA and RNA synthesis. These lesions are consequently strong replication blocks. In addition bulky adducts give rise to point and frameshift mutations. The translesion synthesis (TLS) DNA polymerase η is able to bypass slowly C8 bulky adduct lesions such as the widely studied 2-aminofluorene-dG and its acetylated analogue mainly in an error-free manner. Replicative polymerases are in contrast fully blocked by the acetylated lesion. Here, we show that TLS efficiency of Pol η depends critically on the size of the bulky adduct forming the lesion. Based on the crystal structure, we show why the bypass reaction is so difficult and we provide a model for the bypass reaction. In our model, TLS is accomplished without rotation of the lesion into the anti conformation as previously thought.
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science CIPS, Ludwig-Maximilians University, D-81377 Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schorr
authors.forename: Sabine
authors.initials: S
authors.lastname: Schneider
authors.forename: Katja
authors.initials: K
authors.lastname: Lammens
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
mesh_terms: D015073:2-Acetylaminofluorene / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D000099270:Y-Family DNA Polymerases
chemical_list: D015073:2-Acetylaminofluorene; D018736:DNA Adducts; D004259:DNA-Directed DNA Polymerase; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases