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Perspectives

Molecular and Structural Transactions at Human DNA Replication Origins

Arturo Falaschi, Gulnara Abdurashidova, Oscar Sandoval, Sorina Radulescu, Giuseppe Biamonti and Silvano Riva

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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 pre-replicative complex assembly and topoisomerase I allowing the topological adaptations necessary for initiation of bi-directional synthesis.

Authors

Arturo Falaschi

International Centre for Genetic Engineering and Biotechnology; Trieste, Italy and Scuola Normale Superiore; Istituto di Fisiologia Clinica; Pisa Italy

Gulnara Abdurashidova

International Centre for Genetic Engineering and Biotechnology; Trieste, Italy

Oscar Sandoval

International Centre for Genetic Engineering and Biotechnology; Trieste, Italy

Sorina Radulescu

International Centre for Genetic Engineering and Biotechnology; Trieste, Italy

Giuseppe Biamonti

Istituto di Genetica Molecolare; Pavia, Italy

Silvano Riva

Istituto di Genetica Molecolare; Pavia, Italy

Purchase article for $19

Subscribe to this journal for $129/year