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bioRxiv · 10.1101/2025.06.10.657920

Dynamic regulation of origin firing factors links CDK activity to dormant origin activation

Hossain, M. S.·Sansam, C. G.·Wittig, K. A.·Noble, T. D.·Boyd, K. A.·Sansam, C. L.
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Abstract

Dormant replication origins help ensure complete genome duplication when replication forks stall, yet how these origins are activated remains poorly understood. Here, we identify a novel regulatory mechanism by which cyclin-dependent kinase (CDK) activity controls the abundance and chromatin recruitment of the origin firing factors TRESLIN and MTBP to promote dormant origin activation. Inhibition of WEE1 kinase during S phase increases CDK activity, which blocks the PCNA-dependent degradation of TRESLIN and enhances its chromatin association along with MTBP. This increased loading is required for elevated helicase recruitment and DNA synthesis under CDK-hyperactive conditions. These effects are reversed by CDK inhibition and depend on both TRESLIN and MTBP. We define a conserved sequence within TRESLIN required for its CDK-sensitive degradation. Significantly, the recruitment of TRESLIN-MTBP and loading of helicase exceed levels observed in unperturbed S phase, supporting a model in which dormant origin firing is actively upregulated through CDK-mediated stabilization of the initiation machinery. These findings uncover a new control point in replication origin usage with implications for genome stability and therapeutic kinase inhibition.

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Hossain, M. S., Sansam, C. G., Wittig, K. A., Noble, T. D., Boyd, K. A., Sansam, C. L.. 2025-06-11. Dynamic regulation of origin firing factors links CDK activity to dormant origin activation. https://doi.org/10.1101/2025.06.10.657920

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