Proteolytic control of genome integrity at the replication fork

Faithful duplication of the genome is critical for the survival of an organism and prevention of malignant transformation. Accurate replication of a large amount of genetic information in a timely manner is one of the most challenging cellular processes and is often perturbed by intrinsic and extrinsic barriers to DNA replication fork progression, a phenomenon referred to as DNA replication stress. Elevated DNA replication stress is a primary source of genomic instability and one of the key hallmarks of cancer. Therefore, targeting DNA replication stress is an emerging concept for cancer therapy. The replication machinery associated with PCNA and other regulatory factors coordinates the synthesis and repair of DNA strands at the replication fork. The dynamic interaction of replication protein complexes with DNA is essential for sensing and responding to various signaling events relevant to DNA replication and damage. Thus, the disruption of the spatiotemporal regulation of protein homeostasis at the replication fork impairs genome integrity, which often involves the deregulation of ubiquitin-mediated proteolytic signaling. Notably, emerging evidence has highlighted the role of the AAA + ATPase VCP/p97 in extracting ubiquitinated protein substrates from the chromatin and facilitating the turnover of genome surveillance factors during DNA replication and repair. Here, we review recent advances in our understanding of chromatin-associated degradation pathways at the replication fork and the implication of these findings for cancer therapy.