title: A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA.
abstract: Werner syndrome (WS) is a premature aging disorder where the affected individuals appear much older than their chronological age. The single gene that is defective in WS encodes a protein (WRN) that has ATPase, helicase and 3'-->5' exonuclease activities. Our laboratory has recently uncovered a physical and functional interaction between WRN and the Ku heterodimer complex that functions in double-strand break repair and V(D)J recombination. Importantly, Ku specifically stimulates the exonuclease activity of WRN. We now report that Ku enables the Werner exonuclease to digest through regions of DNA containing 8-oxoadenine and 8-oxoguanine modifications, lesions that have previously been shown to block the exonuclease activity of WRN alone. These results indicate that Ku significantly alters the exonuclease function of WRN and suggest that the two proteins function concomitantly in a DNA damage processing pathway. In support of this notion we also observed co-localization of WRN and Ku, particularly after DNA damaging treatments.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Orren
authors.forename: A
authors.initials: A
authors.lastname: Machwe
authors.forename: P
authors.initials: P
authors.lastname: Karmakar
authors.forename: J
authors.initials: J
authors.lastname: Piotrowski
authors.forename: M P
authors.initials: MP
authors.lastname: Cooper
authors.forename: V A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D034961:Antigens, Nuclear; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D005090:Exodeoxyribonucleases; D005092:Exonucleases / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D053484:RecQ Helicases; D051716:Replication Protein A; D000071657:Werner Syndrome Helicase
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C497167:RPA1 protein, human; D051716:Replication Protein A; C002992:8-hydroxyadenine; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D005090:Exodeoxyribonucleases; D005092:Exonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D000225:Adenine