title: Role of human DNA polymerase κ in extension opposite from a cis-syn thymine dimer.
abstract: Exposure of DNA to UV radiation causes covalent linkages between adjacent pyrimidines. The most common lesion found in DNA from these UV-induced linkages is the cis-syn cyclobutane pyrimidine dimer. Human DNA polymerase κ (Polκ), a member of the Y-family of DNA polymerases, is unable to insert nucleotides opposite the 3'T of a cis-syn T-T dimer, but it can efficiently extend from a nucleotide inserted opposite the 3'T of the dimer by another DNA polymerase. We present here the structure of human Polκ in the act of inserting a nucleotide opposite the 5'T of the cis-syn T-T dimer. The structure reveals a constrained active-site cleft that is unable to accommodate the 3'T of a cis-syn T-T dimer but is remarkably well adapted to accommodate the 5'T via Watson-Crick base pairing, in accord with a proposed role for Polκ in the extension reaction opposite from cyclobutane pyrimidine dimers in vivo.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, NY 10029, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vasquez-Del Carpio
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Silverstein
authors.forename: Samer
authors.initials: S
authors.lastname: Lone
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnson
authors.forename: Louise
authors.initials: L
authors.lastname: Prakash
authors.forename: Satya
authors.initials: S
authors.lastname: Prakash
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
mesh_terms: D020029:Base Pairing; D018360:Crystallography, X-Ray; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D011487:Protein Conformation; D011740:Pyrimidine Dimers / Q000737:chemistry* / Q000378:metabolism; D013941:Thymine / Q000737:chemistry* / Q000378:metabolism; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D004259:DNA-Directed DNA Polymerase; D011740:Pyrimidine Dimers; D013941:Thymine; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases