title: Molecular and structural transactions at human DNA replication origins.
abstract: The DNA replication origins of metazoan genomes are the sites of complex sequence-specific protein-DNA interactions determining their precise cycle of activation and deactivation, once only along each cell cycle. Some of the involved proteins have been identified (and particularly the essential six-protein Origin Recognition Complex, ORC) thanks to their homology with the proteins identified in yeast. Whereas in the latter organism ORC has a specific affinity for an origin consensus, metazoan (and human) ORC shows no sequence specificity and no origin consensus is identifiable in their genomes. The modulation of topology around the origin sequence plays an essential role in the function of the human lamin B2 origin and the two topoisomerases interact specifically with it in a cell-cycle modulated way. The two enzymes are never present on the origin at the same time and compete, in different moments of the cell cycle, with the ORC2 subunit for the same sites in the origin area. The topoisomerases could give essential contributions to origin definition, as demonstrated by their capacity to bind specifically, in vitro the lamin B2 origin, either alone (topoisomerase I) or in a multi-protein complex (topoisomerase II). They also play critical roles in the origin activation-deactivation cycle, topoisomerase II probably contributing to attain and/or maintain a topological status fit for prereplicative complex assembly and topoisomerase I allowing the topological adaptations necessary for initiation of bi-directional synthesis.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. falaschi@icgeb.org
authors.forename: Arturo
authors.initials: A
authors.lastname: Falaschi
authors.forename: Gulnara
authors.initials: G
authors.lastname: Abdurashidova
authors.forename: Oscar
authors.initials: O
authors.lastname: Sandoval
authors.forename: Sorina
authors.initials: S
authors.lastname: Radulescu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biamonti
authors.forename: Silvano
authors.initials: S
authors.lastname: Riva
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D004261:DNA Replication; D026942:DNA Topoisomerases / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D051738:Origin Recognition Complex / Q000235:genetics / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D034921:Lamin Type B; D051738:Origin Recognition Complex; D026942:DNA Topoisomerases