Journal
NUCLEIC ACIDS RESEARCH
Volume 37, Issue 17, Pages 5714-5724Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkp617
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Funding
- Canadian Institute of Health Research
- Canadian Cancer Society/National Institute of Cancer of Canada
- McGill Faculty of Medicine
- Roland and Marcel Gosselin
- Victor K. S. Lui Fellowship
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Initiation of DNA replication involves the ordered assembly of the multi-protein pre-replicative complex (pre-RC) during G(1) phase. Previously, DNA topoisomerase II (topo II) was shown to associate with the DNA replication origin located in the lamin B2 gene locus in a cell-cycle-modulated manner. Here we report that activation of both the early-firing lamin B2 and the late-firing hOrs8 human replication origins involves DNA topo II-dependent, transient, site-specific dsDNA-break formation. Topo II beta in complex with the DNA repair protein Ku associates in vivo and in vitro with the pre-RC region, introducing dsDNA breaks in a biphasic manner, during early and mid-G(1) phase. Inhibition of topo II activity interferes with the pre-RC assembly resulting in prolonged G(1) phase. The data mechanistically link DNA topo II beta-dependent dsDNA breaks and the components of the DNA repair machinery with the initiation of DNA replication and suggest an important role for DNA topology in origin activation.
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