p21 levels in S phase are low but sufficient to prevent pol κ loading to replication forks. When p21 is absent, the abnormal use of pol κ during unperturbed replication impairs nascent DNA elongation. While origin firing increases to compensate the slow fork progression, late replicating and origin-poor DNA regions, that is. CFS, are inefficiently duplicated. The replication defects accumulated in p21-depleted samples lead to genomic instability and transmission of replication defects to G1.