Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms19082376
Keywords
DNA replication; S phase; origin firing; TopBP1; ATR; DNA fiber assay
Funding
- Academy of Finland [251576]
- Finnish Cultural Foundation, North Carelia Regional fund
- UFA by the German Federal Office for Radiation Protection as part of the Kompetenzverbund fur Strahlenforschung [3610S30016]
- Federal Government of Germany
- State of Thuringia
- Leibniz Insitute on Aging-Fritz Lipmann Institute
- Academy of Finland (AKA) [251576, 251576] Funding Source: Academy of Finland (AKA)
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The mammalian DNA replication program is controlled at two phases, the licensing of potential origins of DNA replication in early gap 1 (G1), and the selective firing of a subset of licenced origins in the synthesis (S) phase. Upon entry into the S phase, serine/threonine-protein kinase ATR (ATR) is required for successful completion of the DNA replication program by limiting unnecessary dormant origin activation. Equally important is its activator, DNA topoisomerase 2-binding protein 1 (TopBP1), which is also required for the initiation of DNA replication after a rise in S-phase kinase levels. However, it is unknown how the ATR activation domain of TopBP1 affects DNA replication dynamics. Using human cells conditionally expressing a TopBP1 mutant deficient for ATR activation, we show that functional TopBP1 is required in suppressing local dormant origin activation. Our results demonstrate a regulatory role for TopBP1 in the local balancing of replication fork firing within the S phase.
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