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The Diffley Lab
Chromosome Replication
G1-S and its misregulation in cancer
Human cell cycle control of G1
Regulation of G1 phase of the human cell cycle involves different families of proteins such as RB, CDKs, cyclins, CDK inhibitors and E3 ubiquitin ligases. CDK activity restricts DNA replication initiation outside of S phase, but paradoxically a certain level of CDK is required for human G1 phase progression. We have shown that cyclin E-CDK2 activity prevents APC/C-dependent proteolysis of the essential licensing factor CDC6 when cells reenter the cell cycle from quiescence [Mailand and Diffley, 2005]. We are now investigating how CDK inhibitors such as p27 and p21 are expressed to regulate G1 CDK activity when errors occur in the previous cell cycle.
Figure. Cell cycle regulation (taken from Diffley, 2004)
The Misregulation of Initiation in Cancer
We have contributed over the years to understanding of how replication initiation is regulated by protein kinases including CDK, Dbf4 dependent kinase (DDK) and the DNA damage checkpoint kinase. CDK plays two opposing roles in initiation: It inhibits MCM loading and is essential for MCM activation. Consequently, MCM loading is limited to G1 phase when CDK activity is low. We are especially interested in understanding how compromising this low CDK period by deregulating CDK activity leads to replicative stress and genome doubling (Zeng et al, 2023).
Figure. Model of cyclin E-induced whole genome duplication (taken from Zeng et al, 2023)
Relevant Papers
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Mailand, N. & Diffley, J. F. X. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122, 915–926 (2005).
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Zeng, J., Hills, S. A., Ozono, E. & Diffley, J. F. X. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell 186, 528-542.e14 (2023).
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Diffley, J. F. X. Regulation of early events in chromosome replication. Current Biology 14, 778–786 (2004).
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