Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing.

Although MTBP is essential for replication origin firing, we show here that strong depletion of MTBP can have minor effects on DNA replication rates. This suggests an adaptive process in the DNA replication program, so we examined mechanisms underlying this plasticity. Using an auxin-inducible degron to deplete MTBP, we found that acute suppression of MTBP blocked DNA replication, but that replication rates recovered over time. The timing of this recovery paralleled S phase expression of Cyclin B1, and inhibition of CDK1-Cyclin B1 prevented the recovery. Recovery did not involve restoration of origin firing; instead, replication recovered through accelerated fork progression. Consistent with CDK1 driving this acceleration, ATR inhibition, which activates CDK1, stimulated DNA replication in MTBP-depleted cells through CDK1-dependent increased fork progression rather than increased origin firing. Knockdown of RIF1, a known CDK1 target, phenocopied this effect. Although RIF1 is best known for opposing DDK-dependent MCM phosphorylation at origins, we find that RIF1 knockdown stimulates replication even when DDK is inhibited. Furthermore, RIF1 loss increased replication by accelerating fork progression rather than increasing origin firing. Together, these findings reveal a CDK1-RIF1-dependent mechanism that promotes fork speed during S phase and defines a form of replication plasticity in which fork rate compensates for reduced origin firing.