The ubiquitin-selective chaperone CDC-48/p97, a new player in DNA replication

To ensure duplication of the entire genome, eukaryotic DNA replication initiates from thousands of replication origins. The replication forks move through the chromatin until they encounter forks from neighboring origins. During replication fork termination forks converge, the replisomes disassemble and topoisomerase II resolves the daughter DNA molecules. If not resolved efficiently, terminating forks result in genomic instability through the formation of pathogenic structures. Our recent findings shed light onto the mechanism of replisome disassembly upon replication fork termination. We have shown that termination-specific polyubiquitylation of the replicative helicase component – Mcm7, leads to dissolution of the active helicase in a process dependent on the p97/VCP/Cdc48 segregase. The inhibition of terminating helicase disassembly resulted in a replication termination defect. In this extended view we present hypothetical models of replication fork termination and discuss remaining and emerging questions in the DNA replication termination field.

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“…elegans (95,96). Secondly, the fate of ubiquitylated Mcm7 after being removed from chromatin still remains unknown.…”

Section: P97 Segregase and The Fate Of Ubiquitylated Cmgmentioning

confidence: 99%

Termination of DNA replication forks: “Breaking up is hard to do”

Bailey

Moreno

Gambus

2015

Nucleus

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“…Interestingly, our recent findings identified an essential role for the chaperone-like ATPase CDC-48 in DNA replication that is linked to cell cycle progression (Deichsel et al, 2009; Mouysset et al, 2008). C. elegans CDC-48 and its orthologs in other species (termed Cdc48p in yeast and p97 in vertebrates) mediate mobilization and targeting of ubiquitylated proteins to the 26S proteasome (Rape et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication

et al. 2011

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SUMMARY Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors including CDC-45 and GINS. During the elongation step the CDC-45/GINS complex moves with the replication fork, however it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48UFD-1/NPL-4 deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.

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“…8,12,14,15,[57][58][59] In addition to its regulation of the DDR after DSBs 8 and of Aurora B on mitotic chromosomes, 12 p97 helps to initiate DNA replication, effect protein turnover following UV lesions, arrest DNA replication or transcription machinery and regulate transcription.…”

Section: Mechanism Of P97 Ubiquitindependent Segregase Activity In Chmentioning

confidence: 99%

p97/VCP- and Lys48-linked polyubiquitination form a new signaling pathway in DNA damage response

Ramadan

2012

Cell Cycle

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R NF8/RNF168-dependentLys63-linked polyubiquitination at sites of DNA double-strand breaks (DSBs) was originally regarded as the sole ubiquitin-signaling pathway involved in the DNA damage response (DDR). However, ubiquitin-dependent p97/VCP segregase activity and RNF8-dependent Lys48-linked polyubiquitin chains at DSB sites have recently been identified as components of an additional and parallel ubiquitin-signaling DDR pathway. This newly identified pathway is essential to spatiotemporal protein turnover and regulates both main branches of DSB repair, homologous recombination and nonhomologous end joining. In this report, the function of the RNF8/Lys48 polyubiquitin chains/p97 pathway is discussed in the context of DSB repair and p97 chromatin-related functions.

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The ubiquitin-selective chaperone CDC-48/p97, a new player in DNA replication

Cited by 22 publications

References 43 publications

Termination of DNA replication forks: “Breaking up is hard to do”

Termination of DNA replication forks: “Breaking up is hard to do”

CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication

p97/VCP- and Lys48-linked polyubiquitination form a new signaling pathway in DNA damage response

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