Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication

Abstract

Genome amplification (DNA synthesis) is one of the most demanding cellular processes in all proliferative cells. The DNA replication machinery (also known as the replisome) orchestrates genome amplification during S-phase of the cell cycle. Genetic material is particularly vulnerable to various events that can challenge the replisome during its assembly, activation (firing), progression (elongation) and disassembly from chromatin (termination). Any disturbance of the replisome leads to stalling of the DNA replication fork and firing of dormant replication origins, a process known as DNA replication stress. DNA replication stress is considered to be one of the main causes of sporadic cancers and other pathologies related to tissue degeneration and ageing. The mechanisms of replisome assembly and elongation during DNA synthesis are well understood. However, once DNA synthesis is complete, the process of replisome disassembly, and its removal from chromatin, remains unclear. In recent years, a growing body of evidence has alluded to a central role in replisome regulation for the ubiquitin-dependent protein segregase p97, also known as valosin-containing protein (VCP) in metazoans and Cdc48 in lower eukaryotes. By orchestrating the spatiotemporal turnover of the replisome, p97 plays an essential role in DNA replication. In this review, we will summarise our current knowledge about how p97 controls the replisome from replication initiation, to elongation and finally termination. We will also further examine the more recent findings concerning the role of p97 and how mutations in p97 cofactors, also known as adaptors, cause DNA replication stress induced genomic instability that leads to cancer and accelerated ageing. To our knowledge, this is the first comprehensive review concerning the mechanisms involved in the regulation of DNA replication by p97.

Cohesin Ubiquitylation and Mobilization Facilitate Stalled Replication Fork Dynamics

“…In particular, ubiquitin conjugation has been shown to regulate the function of key replication proteins through modification of their molecular interactions, exclusion from chromatin, or induction of their degradation. This is often achieved via ubiquitin readers or factors targeting ubiquitylated proteins, such as the Cdc48/p97 segregase (Ramadan et al, 2017). Here we report a role for the Rsp5 Bul2 ligase in promoting stable stalled fork progression in a mechanism involving cohesin function, which is likely modulated through its ubiquitylation and mobilization from replicating chromatin.…”

PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress

“…DVC1 regulates PCNA monoubiquitination and TLS polymerase extraction from PCNA-Ub [12,13,48,49]. The SprT-like metallopeptidase domain of DVC1 is associated with counteracting replication stress, premature aging, and tumorigenesis [50,51]. Targeting of Wss1 to DNA lesions requires DNA and SUMO interactions, whereas DVC1 utilizes the interaction with PCNA and ubiquitin via its PIP box and UBZ4 domain [12,52].…”

Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

“…RJALS is caused by monogenic and biallelic mutations in SPRTN ( DVC1 ), and a single missense mutation in a putative metalloprotease SprT domain (SPRTN Y117C ) is pathogenic and responsible for premature aging and liver cancer in humans (Lessel et al., 2014, Ramadan et al., 2016). While the roles of the C-terminal domains of SPRTN have been extensively characterized in translesion DNA synthesis and recruitment to DNA damage foci, the function of the SprT domain, localized in the N-terminal part, is completely unknown (Centore et al., 2012, Davis et al., 2012, Ghosal et al., 2012, Mosbech et al., 2012).…”