title: Nascent DNA Proteomics Reveals a Chromatin Remodeler Required for Topoisomerase I Loading at Replication Forks.
abstract: During transcription and DNA replication, the DNA template is overwound ahead of RNA and DNA polymerases and relaxed by DNA topoisomerases. Inhibitors of topoisomerases are potent anti-cancer agents. Camptothecin traps topoisomerase I on DNA and exerts preferential cytotoxicity toward cancer cells by way of its interference with the progression of replication forks. Starting with an unbiased proteomic analysis, we find that the chromatin remodeling complex BAZ1B-SMARCA5 accumulates near replication forks in camptothecin-exposed cells. We report that BAZ1B associates with topoisomerase I and facilitates its access to replication forks. Single-molecule analyses of replication structures show that BAZ1B contributes to replication interference by camptothecin. A lack of BAZ1B confers increased cellular tolerance of camptothecin. These findings reveal BAZ1B as a key facilitator of topoisomerase I function during DNA replication that affects the response of cancer cells to topoisomerase I inhibitors.
authors.affiliation: Institute of Human Genetics, Centre National de la Recherche Scientifique (CNRS) UPR 1142, University of Montpellier, 34396 Montpellier, France. Electronic address: cyril.ribeyre@igh.cnrs.fr.
authors.forename: Cyril
authors.initials: C
authors.lastname: Ribeyre
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zellweger
authors.affiliation: Institute of Human Genetics, Centre National de la Recherche Scientifique (CNRS) UPR 1142, University of Montpellier, 34396 Montpellier, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Chauvin
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U1194, University of Montpellier, 34298 Montpellier, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bec
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, INSERM, U1194, University of Montpellier, 34298 Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Larroque
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Massimo
authors.initials: M
authors.lastname: Lopes
authors.affiliation: Institute of Human Genetics, Centre National de la Recherche Scientifique (CNRS) UPR 1142, University of Montpellier, 34396 Montpellier, France. Electronic address: angelos.constantinou@igh.cnrs.fr.
authors.forename: Angelos
authors.initials: A
authors.lastname: Constantinou
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D040901:Proteomics / Q000379:methods*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000092468:Bromodomain Containing Proteins
chemical_list: D000251:Adenosine Triphosphatases; D002166:Camptothecin; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004264:DNA Topoisomerases, Type I; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins; C409462:SMARCA5 protein, human; C528909:TOP1 protein, human