title: DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression.
abstract: DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, D-89075 Ulm, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hampp
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, D-89075 Ulm, Germany;
authors.forename: Tina
authors.initials: T
authors.lastname: Kiessling
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, D-89075 Ulm, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Buechle
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir-Instituto de Investigaciones Bioquimicas de Buenos Aires, National Scientific and Technical Research Council, Buenos Aires C1405BWE, Argentina;
authors.forename: Sabrina F
authors.initials: SF
authors.lastname: Mansilla
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, D-45122 Essen, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, D-89075 Ulm, Germany;
authors.forename: Melanie
authors.initials: M
authors.lastname: Rall
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027;
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Research Group Biochemistry, Leibniz Institute on Aging-Fritz Lipmann Institute, D-07745 Jena, Germany; Faculty of Biochemistry and Molecular Medicine, University of Oulu, FIN-90014, Oulu, Finland.
authors.forename: Helmut
authors.initials: H
authors.lastname: Pospiech
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir-Instituto de Investigaciones Bioquimicas de Buenos Aires, National Scientific and Technical Research Council, Buenos Aires C1405BWE, Argentina;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gottifredi
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, D-89075 Ulm, Germany; lisa.wiesmueller@uni-ulm.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D059765:Homologous Recombination; D006801:Humans; D020014:K562 Cells; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000094769:DNA Polymerase iota
chemical_list: D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D051716:Replication Protein A; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D004265:DNA Helicases; C555409:ZRANB3 protein, human; D000094769:DNA Polymerase iota; C000722070:POLI protein, human
keywords: DNA damage bypass; DNA polymerase idling; nascent DNA elongation; p53; polymerase ι