The Depletion of TRAIP Results in the Retention of PCNA on Chromatin During Mitosis Leads to Inhibiting DNA Replication Initiation

Abstract

Loading PCNA onto chromatin is a pivotal step in DNA replication, cell cycle progression, and genome integrity. Conversely, unloading PCNA from chromatin is equally crucial for maintaining genome stability. Cells deficient in the PCNA unloader ATAD5-RFC exhibit elevated levels of chromatin-bound PCNA during S phase, but still show dissociation of PCNA from chromatin in mitosis. In this study, we found that depletion of TRAIP, an E3 ubiquitin ligase, results in the retention of PCNA on chromatin during mitosis. Although TRAIP-depleted cells with chromatin-bound PCNA during mitosis progressed into the subsequent G1 phase, they displayed reduced levels of Cdt1, a key replication licensing factor, and impaired S phase entry. In addition, TRAIP-depleted cells exhibited delayed S phase progression. These results suggest that TRAIP functions independently of ATAD5-RFC in removing PCNA from chromatin. Furthermore, TRAIP appears to be essential for precise pre-replication complexes (pre-RCs) formation necessary for faithful initiation of DNA replication and S phase progression.