Loss of G1-phase CDK-inhibition biases instability between genomic regions by unevenly reducing activity among replication origins

Most cancer cells deregulate the pathway that prevents premature CDK activation in late G1. When this occurs, replication stress, under-replication, and chromosomal instability ensue, with heterogeneous genomic incidence by poorly understood mechanisms. Using budding yeast as a model, here we show that depletion of the CDK-inhibitor Sic1, which controls G1/S phase transition, unevenly impairs replication and stability of genomic regions by irregularly reducing activity across replication origins. This induces variable regional concentration of defective origins. Deficiency of neighboring active and dormant origins within a region reduces origin redundancy to increase local instability due to unrestricted mitosis entry with ongoing DNA synthesis, but without inducing an S-phase checkpoint response. In contrast, when a single active origin is defective within unaffected dormant origins, only minor regional under-replication and instability ensue. These findings suggest that CDK-inhibition loss during G1 induces differential under-replication and instability across the genome by heterogeneously diminishing replication origin redundancy.