CDC-48/p97 Coordinates CDT1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication

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Franz, André ; Orth, Michael ; Pirson, Paul A. ; Sonneville, Remi ; Blow, J. Julian ; Gartner, Anton ; Stemmann, Olaf ; Hoppe, Thorsten:
CDC-48/p97 Coordinates CDT1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication.
In: Molecular Cell. Bd. 44 (7 Oktober 2011) Heft 1 . - S. 85-96.
ISSN 1097-4164
DOI: https://doi.org/10.1016/j.molcel.2011.08.028

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Abstract

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-48(UFD-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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